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1. Phenotypic characterization of seven individuals with <scp>Marbach–Schaaf</scp> neurodevelopmental syndrome

Author: Felix Marbach, Beata S. Lipska‐Ziętkiewicz, Agata Knurowska, Vincent Michaud, Henri Margot, James Lespinasse, Frédéric Tran Mau Them, Christine Coubes, Joohyun Park, Sarah Grosch, Cristiana Roggia, Ute Grasshoff, Louisa Kalsner, Anne‐Sophie Denommé‐Pichon, Alexandra Afenjar, Bénédicte Héron, Boris Keren, Pilar Caro, Christian P. Schaaf, Heidelberg University, University of Gdańsk (UG), Medical University of Gdańsk, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Tübingen, School of Medicine [University of Connecticut], University of Connecticut (UCONN), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Baylor College of Medicine (BCM), Baylor University, and Admin, Oskar
Subjects: Adult, Pain insensitivity, Autism Spectrum Disorder, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Global developmental delay, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Syndrome, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Cohort Studies, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Phenotype, Neurodevelopmental disorder, PRKAR1B, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Genetics, Protein kinase a complex, Animals, Humans, Genetics (clinical)
Abstract: International audience; We present the phenotypes of seven previously unreported patients with Marbach-Schaaf neurodevelopmental syndrome, all carrying the same recurrent heterozygous missense variant c.1003C>T (p.Arg335Trp) in PRKAR1B. Clinical features of this cohort include global developmental delay and reduced sensitivity to pain, as well as behavioral anomalies. Only one of the seven patients reported here was formally diagnosed with autism spectrum disorder (ASD), while ASD-like features were described in others, overall indicating a lower prevalence of ASD in Marbach-Schaaf neurodevelopmental syndrome than previously assumed. The clinical spectrum of the current cohort is similar to that reported in the initial publication, delineating a complex developmental disorder with behavioral and neurologic features. PRKAR1B encodes the regulatory subunit R1beta of the protein kinase A complex (PKA), and is expressed in the adult and embryonal central nervous system in humans. PKA is crucial to a plethora of cellular signaling pathways, and its composition of different regulatory and catalytic subunits is cell-type specific. We discuss potential molecular disease mechanisms underlying the patients' phenotypes with respect to the different known functions of PKA in neurons, and the phenotypes of existing R1beta-deficient animal models.
Published: 2022

2. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

Author: Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Julien Thevenon, Hana Safraou, Thomas Besnard, Alice Goldenberg, Benjamin Cogné, Bertrand Isidor, Julian Delanne, Arthur Sorlin, Sébastien Moutton, Mélanie Fradin, Christèle Dubourg, Magali Gorce, Dominique Bonneau, Salima El Chehadeh, François-Guillaume Debray, Martine Doco-Fenzy, Kevin Uguen, Nicolas Chatron, Bernard Aral, Nathalie Marle, Paul Kuentz, Anne Boland, Robert Olaso, Jean-François Deleuze, Damien Sanlaville, Patrick Callier, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Antonio Vitobello, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, CHU Dijon, Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Institut du Thorax [Nantes], Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Hospices Civils de Lyon (HCL), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), the European Union through the FEDER programs (PERSONALISE), and the Burgundy-Franche Comté regional council (INTEGRA). The sequencing performed at the CNRGH was supported by the France Génomique National infrastructure, funded as part of the 'Investissements d’Avenir' program managed by the Agence Nationale pour la Recherche (contract ANR-10-INBS-09)., and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cell Biology, Developmental Biology
Abstract: Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches.Methods: In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%–9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%–6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis.Results: SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization.Conclusion: Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.
Published: 2023

3. iPSCs derived from infertile men carrying complex genetic abnormalities can generate primordial germ-like cells

Author: Aurélie Mouka, Brahim Arkoun, Pauline Moison, Loïc Drévillon, Rafika Jarray, Sophie Brisset, Anne Mayeur, Jérôme Bouligand, Anne Boland-Auge, Jean-François Deleuze, Frank Yates, Thomas Lemonnier, Patrick Callier, Yannis Duffourd, Patrick Nitschke, Emmanuelle Ollivier, Arnaud Bourdin, John De Vos, Gabriel Livera, Gérard Tachdjian, Leïla Maouche-Chrétien, Lucie Tosca, AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Saclay, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Site de recherche intégrée en cancérologie (SiRIC CURAMUS), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sup'Biotech, Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), MORNET, Dominique, and Institut Universitaire de Cancérologie [Paris] (IUC)
Subjects: [SDV] Life Sciences [q-bio], Male, Multidisciplinary, Germ Cells, Erythroblasts, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Humans, Cell Differentiation, Azoospermia
Abstract: Despite increasing insight into the genetics of infertility, the developmental disease processes remain unclear due to the lack of adequate experimental models. The advent of induced pluripotent stem cell (iPSC) technology has provided a unique tool for in vitro disease modeling enabling major advances in our understanding of developmental disease processes. We report the full characterization of complex genetic abnormalities in two infertile patients with either azoospermia or XX male syndrome and we identify genes of potential interest implicated in their infertility. Using the erythroblasts of both patients, we generated primed iPSCs and converted them into a naive-like pluripotent state. Naive-iPSCs were then differentiated into primordial germ-like cells (PGC-LCs). The expression of early PGC marker genes SOX17, CD-38, NANOS3, c-KIT, TFAP2C, and D2-40, confirmed progression towards the early germline stage. Our results demonstrate that iPSCs from two infertile patients with significant genetic abnormalities are capable of efficient production of PGCs. Such in vitro model of infertility will certainly help identifying causative factors leading to early germ cells development failure and provide a valuable tool to explore novel therapeutic strategies.
Published: 2022

4. Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy

Author: Myriam Vezain, Christel Thauvin-Robinet, Yoann Vial, Sophie Coutant, Séverine Drunat, Jon Andoni Urtizberea, Anne Rolland, Agnès Jacquin-Piques, Séverine Fehrenbach, Gaël Nicolas, François Lecoquierre, Pascale Saugier-Veber, Julien, Sabine, Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Cancer and Brain Genomics (CBG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier de Valence, Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Genetics (clinical)
Abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting from biallelic alterations of the SMN1 gene: deletion, gene conversion or, in rare cases, intragenic variants. The disease severity is mainly influenced by the copy number of SMN2, a nearly identical gene, which produces only low amounts of full-length (FL) mRNA. Here we describe the first example of retrotransposon insertion as a pathogenic SMN1 mutational event. The 50-year-old patient is clinically affected by SMA type III with a diagnostic odyssey spanning nearly 30 years. Despite a mild disease course, he carries a single SMN2 copy. Using Exome Sequencing and Sanger sequencing, we characterized a SVA-F retrotransposon inserted in SMN1 intron 7. Using RT-PCR and RNASeq experiments on lymphoblastoid cell lines, we documented the dramatic decrease of FL transcript production in the patient compared to subjects with the same SMN1 and SMN2 copy number, thus validating the pathogenicity of this SVA insertion. We characterized the mutant FL-SMN1-SVA transcript and showed that it is subject to degradation by nonsense-mediated mRNA decay. The stability of the SMN-SVA protein may explain the mild course of the disease. This observation exemplifies the role of retrotransposons in human genetic disorders.
Published: 2022

5. The economic, medical and psychosocial consequences of whole genome sequencing for the genetic diagnosis of patients with intellectual disability: The DEFIDIAG study protocol

Author: Catherine Lejeune, Charley Robert-Viard, Nicolas Meunier-Beillard, Myriam Alice Borel, Léna Gourvès, Stéphanie Staraci, Anne-Laure Soilly, Francis Guillemin, Valerie Seror, Hamza Achit, Marion Bouctot, Marie-Laure Asensio, Anne-Sophie Briffaut, Christelle Delmas, Ange-Line Bruel, Alexia Benoit, Alban Simon, Bénédicte Gerard, Hamza Hadj Abdallah, Stanislas Lyonnet, Laurence Faivre, Christel Thauvin-Robinet, Sylvie Odent, Delphine Heron, Damien Sanlaville, Thierry Frebourg, Jean Muller, Yannis Duffourd, Anne Boland, Jean-François Deleuze, Hélène Espérou, Christine Binquet, Hélène Dollfus, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe EPICAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Délégation à la recherche clinique et à l'innovation [CHU Dijon] (DRCI), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pôle de Recherche Clinique [Paris] (PRC), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), FHU TRANSLAD (CHU de Dijon), Equipe GAD (LNC - U1231), Institut de génétique médicale, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), TheDEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. Institut national de la santé et de la recherche médicale (Inserm) is the sponsor of the DEFDIAG study., COMBE, Isabelle, and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, micro-costing, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, genome sequencing, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, intellectual disability, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Molecular Medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, cost-effectiveness, Genetics (clinical), [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, qualitative stud
Abstract: Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1–3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS.Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses.Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)—identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361).Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).
Published: 2022

6. Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study

Author: Guillaume Jouret, Solveig Heide, Arthur Sorlin, Laurence Faivre, Sandra Chantot‐Bastaraud, Claire Beneteau, Marie Denis‐Musquer, Peter D. Turnpenny, Charles Coutton, Gaëlle Vieville, Julien Thevenon, Austin Larson, Florence Petit, Elise Boudry, Thomas Smol, Bruno Delobel, Bénédicte Duban‐Bedu, Chiara Fallerini, Francesca Mari, Caterina Lo Rizzo, Alessandra Renieri, Jean‐Hubert Caberg, Anne‐Sophie Denommé‐Pichon, Frédéric Tran Mau‐Them, Isabelle Maystadt, Thomas Courtin, Boris Keren, Linda Mouthon, Perrine Charles, Silvestre Cuinat, Bertrand Isidor, Philippe Theis, Christian Müller, Marizela Kulisic, Seval Türkmen, Daniel Stieber, Dominique Bourgeois, Emmanuel Scalais, Barbara Klink, Couvet, Sandrine, Laboratoire National de Santé [Luxembourg] (LNS), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), UF de Génétique chromosomique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Laboratoire de Génétique Chromosomique [CHU de Grenoble], CHU Grenoble, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Siena = University of Siena (UNISI), Azienda Ospedaliera Universitaria Senese, Centre Hospitalier Universitaire de Liège (CHU-Liège), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre de Génétique Humaine [Charleroi, Belgium] (Institut de Pathologie et de Génétique), Institut de Pathologie et de Génétique, Charleroi, Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Centre Hospitalier de Luxembourg [Luxembourg] (CHL)
Subjects: MESH: Mutation, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, NIPBL, BRD4-related syndrome, cohesinopathy, MESH: Cell Cycle Proteins, MESH: Pregnancy, Pregnancy, MESH: Child, De Lange Syndrome, Genetics, Humans, Child, Genetics (clinical), MESH: Humans, MESH: Genomics, Nuclear Proteins, MESH: Transcription Factors, Genomics, Cornelia de Lange syndrome, [SDV] Life Sciences [q-bio], Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, BRD4, Female, MESH: Female, MESH: Nuclear Proteins, MESH: De Lange Syndrome, Transcription Factors
Abstract: International audience; BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies.
Published: 2022

7. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

Author: Cyril Goizet, Arthur Sorlin, Antonio Novelli, Christophe Philippe, Mathilde Nizon, Joan M. Stoler, Maria J. Guillen Sacoto, Marielle Alders, Grace Yoon, Binnaz Yalcin, Aurélien Trimouille, Anna R. Duncan, Valerie E. Vancollie, Emanuele Agolini, Lance H. Rodan, Monica H. Wojcik, Christopher J. Lelliott, Saskia M. Maas, Antonio Vitobello, Pankaj B. Agrawal, Ange Line Bruel, Laurence Faivre, Paolo Prontera, Stephan C. Collins, Teresa Santiago-Sim, Casie A. Genetti, Ann Seman, Jiahai Shi, Marieke F. van Dooren, Patricia Ellen Grant, Clinical Genetics, Boston Children's Hospital, Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD (CHU de Dijon), The Wellcome Trust Sanger Institute [Cambridge], City University of Hong Kong [Hong Kong] (CUHK), Bambino Gesù Children’s Hospital [Rome, Italy], Università degli Studi di Perugia = University of Perugia (UNIPG), GeneDx [Gaithersburg, MD, USA], Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre hospitalier universitaire de Nantes (CHU Nantes), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Amsterdam UMC - Amsterdam University Medical Center, Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon) (CRMR des déficiences intellectuelles de causes rares), The Hospital for sick children [Toronto] (SickKids), Dupuis, Christine, Human Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, ACS - Pulmonary hypertension & thrombosis, Amsterdam Reproduction & Development (AR&D), Lelliott, Christopher [0000-0001-8087-4530], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Jumonji Domain-Containing Histone Demethylases, [SDV]Life Sciences [q-bio], Developmental Disabilities, Corpus callosum, Hippocampus, Epigenesis, Genetic, Histones, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Polymicrogyria, Global developmental delay, Agenesis of the corpus callosum, Genetics (clinical), Brain, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], intellectual disability, Brain size, Female, dysmorphic hippocampi, Signal Transduction, Heterozygote, heterozygous variant, global developmental delay, Biology, Nervous System Malformations, Methylation, 03 medical and health sciences, Seizures, Report, KDM4B, Genetics, medicine, Animals, Humans, neurodevelopmental disorder, Dentate gyrus, Genetic Variation, JMJD2B, medicine.disease, 030104 developmental biology, agenesis of the corpus callosum, Neuroscience, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Ventriculomegaly
Abstract: International audience; KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b þ/À), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.
Published: 2020

8. SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance

Author: Amélie Cordovado, Martina Schaettin, Médéric Jeanne, Veranika Panasenkava, Anne-Sophie Denommé-Pichon, Boris Keren, Cyril Mignot, Martine Doco-Fenzy, Lance Rodan, Keri Ramsey, Vinodh Narayanan, Julie R Jones, Eloise J Prijoles, Wendy G Mitchell, Jillian R Ozmore, Kali Juliette, Erin Torti, Elizabeth A Normand, Leslie Granger, Andrea K Petersen, Margaret G Au, Juliann P Matheny, Chanika Phornphutkul, Mary-Kathryn Chambers, Joaquín-Alejandro Fernández-Ramos, Eduardo López-Laso, Michael C Kruer, Somayeh Bakhtiari, Marcella Zollino, Manuela Morleo, Giuseppe Marangi, Davide Mei, Tiziana Pisano, Renzo Guerrini, Raymond J Louie, Anna Childers, David B Everman, Betrand Isidor, Séverine Audebert-Bellanger, Sylvie Odent, Dominique Bonneau, Brigitte Gilbert-Dussardier, Richard Redon, Stéphane Bézieau, Frédéric Laumonnier, Esther T Stoeckli, Annick Toutain, Marie-Laure Vuillaume, Jonchère, Laurent, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Zürich [Zürich] = University of Zurich (UZH), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), The Translational Genomics Research Institute (TGen), The Greenwood Genetic Center, Keck School of Medicine [Los Angeles], University of Southern California (USC), Dartmouth Hitchcock Medical Center [Lebanon], Gillette Children's Specialty Healthcare [St Paul], GeneDx [Gaithersburg, MD, USA], Randall Children's Hospital [Portland], University of Kentucky (UK), Warren Alpert Medical School of Brown University, Rhode Island Hospital [Providence, RI, États-Unis], Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, Barrow Neurological Institute, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Università degli Studi di Firenze = University of Florence (UniFI), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Funding for HUGODIMS (Western France exome-based trio approach project to identifygenes involved in intellectual disability) was supported by a grant from the French Ministryof Health and from the Health Regional Agency from Poitou-Charentes [HUGODIMS, 2013,RC14_0107]. [A.C.] is a research student recipient of a grant from the University of Tours., Cordovado, Amélie, Schaettin, Martina, Jeanne, Médéric, Panasenkava, Veranika, Denommé-Pichon, Anne-Sophie, Keren, Bori, Mignot, Cyril, Doco-Fenzy, Martine, Rodan, Lance, Ramsey, Keri, Narayanan, Vinodh, Jones, Julie R, Prijoles, Eloise J, Mitchell, Wendy G, Ozmore, Jillian R, Juliette, Kali, Torti, Erin, Normand, Elizabeth A, Granger, Leslie, Petersen, Andrea K, Au, Margaret G, Matheny, Juliann P, Phornphutkul, Chanika, Chambers, Mary-Kathryn, Fernández-Ramos, Joaquín-Alejandro, López-Laso, Eduardo, Kruer, Michael C, Bakhtiari, Somayeh, Zollino, Marcella, Morleo, Manuela, Marangi, Giuseppe, Mei, Davide, Pisano, Tiziana, Guerrini, Renzo, Louie, Raymond J, Childers, Anna, Everman, David B, Isidor, Betrand, Audebert-Bellanger, Séverine, Odent, Sylvie, Bonneau, Dominique, Gilbert-Dussardier, Brigitte, Redon, Richard, Bézieau, Stéphane, Laumonnier, Frédéric, Stoeckli, Esther T, Toutain, Annick, and Vuillaume, Marie-Laure
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, Epilepsy, Dendritic Spines, [SDV]Life Sciences [q-bio], Intellectual disability, Chick Embryo, Semaphorins, [SDV.GEN] Life Sciences [q-bio]/Genetics, General Medicine, Settore MED/03 - GENETICA MEDICA, Axon Guidance, [SDV] Life Sciences [q-bio], HEK293 Cells, SEMA6B, Intellectual Disability, Genetics, Animals, Humans, Original Article, Molecular Biology, Genetics (clinical)
Abstract: Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.
Published: 2022

9. High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

Author: Arthur Sorlin, Antonio Vitobello, Benoit Daubail, Christel Thauvin-Robinet, Marie Hervieu-Bègue, Laurence Faivre, Agnès Fromont, Ange-Line Bruel, Frédéric Tran Mau-Them, Thibault Moreau, Julian Delanne, Guy-Victor Osseby, Quentin Thomas, Patrick Callier, Christophe Philippe, Sébastien Moutton, Maurice Giroud, Anne-Sophie Denommé-Pichon, Agnès Jacquin-Piques, Sophie Nambot, Yannis Duffourd, Philippine Garret, Y Béjot, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Neurophysiologie Clinique (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Proband, Pediatrics, medicine.medical_specialty, Movement disorders, Neurology, Neurodegeneration with brain iron accumulation, [SDV]Life Sciences [q-bio], Encephalopathy, Neurogenetics, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Genetics, Humans, Medicine, Exome, Clinical significance, 030212 general & internal medicine, Genetic Testing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Nervous System Diseases, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.
Published: 2021

10. Cystoid maculopathy is a frequent feature of Cohen syndrome-associated retinopathy

Author: Eléonore Lizé, Grazia M.S. Mancini, Christel Thauvin-Robinet, Vincent Lhussiez, Hélène Dollfus, Saddek Mohand-Said, Niyazi Acar, Xavier Zanlonghi, José-Alain Sahel, Pierre-Henry Gabrielle, Isabelle Audo, Emeline F. Nandrot, Laurence Duplomb, Catherine Creuzot-Garcher, Alberta A H J Thiadens, Yaumara Perdomo, Muhammad Ansar, Romain Da Costa, Christina Zeitz, Laurence Faivre, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), DHU Sight Restore [Paris], CHU Pontchaillou [Rennes], Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Institute of Molecular and Clinical Ophthalmology Basel [Basel, Switzerland] (IMCOB), Fondation Asile des aveugles - Hôpital Ophtalmique Jules-Gonin [Lausanne], Centre de Référence Déficiences Intellectuelles de Causes Rares [CHU Dijon] (CRDICR), Service d'Ophtalmologie (CHU de Dijon), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Institute of Molecular and Clinical Ophthalmology Basel, CH-4031 Basel, Switzerland, Jules Gonin Eye Hospital, Université de Lausanne = University of Lausanne (UNIL), Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon) (CRMR des déficiences intellectuelles de causes rares), the Conseil Régional de Bourgogne and the European Union through the Plan d'Actions Régional pour l'Innovation (PARI) and the PO FEDER-FSE Bourgogne 2014/2020 programs. This work is also supported by a research grant from the University of Pennsylvania Orphan Disease Center in partnership with COH1 Research Alliance (L.F., R.D.C., C.T., L.D.), and with funds from the JED Fondation (L.F.) as well as from Ville de Paris and Region Ile de France, LABEX LIFESENSES [reference ANR-10-LABX-65] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program [ANR-11-IDEX-0004–0], IHU FOReSIGHT [ANR-18-IAHU-0001] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program and Foundation Fighting Blindness center grant [C-CMM-0907–0428-INSERM04]., ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), Julien, Sabine, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, Ophthalmology, Clinical Genetics, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Lausanne (UNIL)
Subjects: Male, genetic structures, Developmental Disabilities, Macular Degeneration, 0302 clinical medicine, Myopia, Medicine, Young adult, Child, 0303 health sciences, Multidisciplinary, Retinal Degeneration, Medical genetics, Retinal diseases, 3. Good health, VPS13B, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Preschool, Cohort, Microcephaly, Muscle Hypotonia, Female, Tomography, Optical Coherence, Retinopathy, Adult, medicine.medical_specialty, Adolescent, Science, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Macular Edema, Article, Retina, Fingers, Young Adult, 03 medical and health sciences, Intellectual Disability, Ophthalmology, Humans, Obesity, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retrospective Studies, 030304 developmental biology, Cohen syndrome, business.industry, Dystrophy, Hereditary eye disease, medicine.disease, eye diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, Maculopathy, sense organs, business
Abstract: Cohen syndrome (CS) is a rare syndromic form of rod-cone dystrophy. Recent case reports have suggested that cystoid maculopathy (CM) could affect CS patients with an early onset and high prevalence. Our study aims at improving our understanding and management of CM in CS patients through a retrospective case series of ten CS patients with identified pathogenic variants in VPS13B. Longitudinal optical coherence tomography (OCT) imaging was performed and treatment with carbonic anhydrase inhibitors (CAI) was provided to reduce the volume of cystoid spaces. CM affected eight out of ten patients in our cohort. The youngest patient showed a strong progression of macular cysts from the age of 4.5 to 5 years despite oral CAI medication. Other teenage and young adult patients showed stable macular cysts with and without treatment. One patient showed a moderate decrease of cystoid spaces in the absence of treatment at 22 years of age. Through a correlative analysis we found that the volume of cystoid spaces was positively correlated to the thickness of peripheral and macular photoreceptor-related layers. This study suggests that CAI treatments may not suffice to improve CM in CS patients, and that CM may resolve spontaneously during adulthood as photoreceptor dystrophy progresses.
Published: 2021

11. EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder

Author: Jessica Assoumani, Morgane Plutino, Caroline Benech, Nathalie Marle, Houda Karmous-Benailly, Elise Boudry Labis, Sylvia Redon, Lionel Van Maldergem, Hala Nasser, Nathalie Couque, Myriam Rachid, Anne-Claude Tabet, Bérénice Schell, Aafke Engwerda, Mélanie Rama, Odile Boute, Céline Dupont, Conny M. A. van Ravenswaaij-Arts, Patrick Callier, Lyse Ruaud, Jonathan I. Levy, Paul Kuentz, Alain Verloes, Laurence Faivre, Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University Medical Center Groningen [Groningen] (UMCG), Centre Hospitalier Universitaire de Nice (CHU Nice), EFS, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Lille, Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Institut de génétique médicale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work has been generated within the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]., Clinical Cognitive Neuropsychiatry Research Program (CCNP), PODEUR, Sophie, and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC)
Subjects: Male, Microcephaly, [SDV]Life Sciences [q-bio], 6q16, 1 microdeletion, Inheritance Patterns, EPHA7, Haploinsufficiency, Biology, speech and language development, Neurodevelopmental disorder, Exome Sequencing, Genetics, medicine, Ephrin, Humans, Genetic Predisposition to Disease, microcephaly, Genetics (clinical), Genetic Association Studies, In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, 6q16.1 microdeletion, Erythropoietin-producing hepatocellular (Eph) receptor, Receptor, EphA7, medicine.disease, Penetrance, Phenotype, neurodevelopmental disorder, Pedigree, [SDV] Life Sciences [q-bio], Neurodevelopmental Disorders, intellectual disability, Mutation, Chromosomes, Human, Pair 6, Female
Abstract: International audience; Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We report 12 additional patients from nine unrelated pedigrees with similar deletions. The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance. Four patients had tiny deletions involving only EPHA7, suggesting a critical role of EPHA7 in a neurodevelopmental disability phenotype. We provide further evidence for EPHA7 deletion as a risk factor for neurodevelopmental disorder and delineate its clinical phenotype.
Published: 2021

12. Exome sequencing allows detection of relevant pharmacogenetic variants in epileptic patients

Author: Simon Verdez, Quentin Thomas, Philippine Garret, Céline Verstuyft, Emilie Tisserant, Antonio Vitobello, Frédéric Tran Mau-Them, Christophe Philippe, Marc Bardou, Maxime Luu, Abderrahmane Bourredjem, Patrick Callier, Christel Thauvin-Robinet, Nicolas Picard, Laurence Faivre, Yannis Duffourd, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire CERBA [Saint Ouen l'Aumône], Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, FHU TRANSLAD (CHU de Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Université de Bourgogne (UB)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon) (CRMR des déficiences intellectuelles de causes rares), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), and Duffourd, Yannis
Subjects: Pharmacology, [SDV] Life Sciences [q-bio], Epilepsy, Pharmacogenomic Variants, [SDV]Life Sciences [q-bio], Phenytoin, Genetics, Molecular Medicine, Humans, Exome, Retrospective Studies
Abstract: International audience; Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an "in house" pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytointreated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10-23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.
Published: 2021

13. How to make a tongue: Cellular and molecular regulation of muscle and connective tissue formation during mammalian tongue development

Author: Hadeel Adel Al-Lami, Karen J. Liu, Sachiko Iseki, Martyn T. Cobourne, Guilherme M. Xavier, Christel Thauvin-Robinet, Anahid A. Birjandi, Department of Craniofacial Development & Orthodontics, London Dental Institute (LDI), King‘s College London-King‘s College London, Section of Molecular Craniofacial Embryology (Graduate School of Tokyo Medical and Dental University), Department of Orthodontics (University of Baghdad College of Dentistry), University of Baghdad, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Organogenesis, Hedgehog signaling, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Bifid tongue, Mesoderm, Wnt, 03 medical and health sciences, 0302 clinical medicine, Cranial neural crest, Tongue, Macroglossia, medicine, Animals, Humans, TGF-beta, Hedgehog, Mammals, Aglossia, Muscles, Myogenesis, Gene Expression Regulation, Developmental, Cell Biology, Anatomy, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Connective Tissue, Neural Crest, Embryology, Gross anatomy, medicine.symptom, 030217 neurology & neurosurgery, Signal Transduction, Developmental Biology
Abstract: IF 6.614 (2016); International audience; The vertebrate tongue is a complex muscular organ situated in the oral cavity and involved in multiple functions including mastication, taste sensation, articulation and the maintenance of oral health. Although the gross embryological contributions to tongue formation have been known for many years, it is only relatively recently that the molecular pathways regulating these processes have begun to be discovered. In particular, there is now evidence that the Hedgehog, TGF-Beta, Wnt and Notch signaling pathways all play an important role in mediating appropriate signaling interactions between the epithelial, cranial neural crest and mesodermal cell populations that are required to form the tongue. In humans, a number of congenital abnormalities that affect gross morphology of the tongue have also been described, occurring in isolation or as part of a developmental syndrome, which can greatly impact on the health and well-being of affected individuals. These anomalies can range from an absence of tongue formation (aglossia) through to diminutive (microglossia), enlarged (macroglossia) or bifid tongue. Here, we present an overview of the gross anatomy and embryology of mammalian tongue development, focusing on the molecular processes underlying formation of the musculature and connective tissues within this organ. We also survey the clinical presentation of tongue anomalies seen in human populations, whilst considering their developmental and genetic etiology.
Published: 2019

14. TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation

Author: Julien Thevenon, David Geneviève, Laurence Faivre, C. F. Wells, Yannis Duffourd, camille lemattre, B. Vuadelle, Sophie Nambot, Marjolaine Willems, Paul Kuentz, Emmanuelle Haquet, Pierre Sarda, Ange-Line Bruel, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de génétique et procréation (Grenoble), Centre Hospitalier Universitaire [Grenoble] (CHU), Université Bourgogne Franche-Comté [COMUE] (UBFC), Orphanomix, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), FHU TRANSLAD (CHU de Dijon), Lycée Philippe Lamour (Nîmes), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de Biologie Moléculaire ( CHRU Saint‐Jacques, Besançon), and Hôpital Saint-Jacques [CHRU de Besançon]
Subjects: Male, 0301 basic medicine, Adolescent, Genotype, Receptors, Cytoplasmic and Nuclear, Biology, 03 medical and health sciences, 0302 clinical medicine, PIERPONT SYNDROME, Genetics, Humans, TBL1XR1, Missense mutation, Abnormalities, Multiple, Recurrent mutation, Genetic Testing, Alleles, Genetics (clinical), Exome sequencing, Loss function, Ultrasonography, Comparative Genomic Hybridization, [SDV.GEN]Life Sciences [q-bio]/Genetics, Brain, Facies, Nuclear Proteins, Syndrome, Magnetic Resonance Imaging, Phenotype, 3. Good health, Repressor Proteins, 030104 developmental biology, Amino Acid Substitution, 030220 oncology & carcinogenesis, Mutation, Mutation (genetic algorithm), Pierpont syndrome
Abstract: IF 2.264; International audience; Pierpont syndrome is a rare and sporadic syndrome, including developmental delay, facial characteristics, and abnormal extremities. Recently, a recurrent de novo TBL1XR1 variant (c.1337A > G; p.Tyr446Cys) has been identified in eight patients by whole‐exome sequencing. A dominant‐negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype. We report two patients with typical Pierpont‐like syndrome features. Exome sequencing allowed identifying a de novo heterozygous missense TBL1XR1 variant in both patients, different from those already reported: p.Cys325Tyr and p.Tyr446His. The localization of these mutations and clinical features of Pierpont‐like syndrome suggest that their functional consequences are comparable with the recurrent mutation previously described, and provided additional data to understand molecular mechanisms of TBL1XR1 anomalies.
Published: 2018

15. Superficial Siderosis of the Central Nervous System associated with Hemophilia A: A case report

Author: Yannick Béjot, Maurice Giroud, Sophie Mohr, Guy-Victor Osseby, Gauthier Duloquin, Quentin Thomas, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and CCSD, Accord Elsevier
Subjects: Pathology, medicine.medical_specialty, Central nervous system, lcsh:Surgery, Superficial Siderosis of the Central Nervous System, [INFO] Computer Science [cs], lcsh:RC346-429, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine, Medical history, [INFO]Computer Science [cs], lcsh:Neurology. Diseases of the nervous system, Subclinical infection, etiological diagnosis, Cerebellar ataxia, business.industry, Lumbar spinal stenosis, lcsh:RD1-811, medicine.disease, Spinal cord, Superficial siderosis, 3. Good health, medicine.anatomical_structure, Congenital Hemophilia A, Hemosiderin, chronical bleeding, Surgery, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Superficial Siderosis of the Central Nervous System (SSCNS) is a condition secondary to the deposition of hemosiderin within the subpial layers of central nervous system leading to its progressive degeneration, clinically responsible for hearing impairment, cerebellar ataxia and pyramidal syndrome. Here we report the case of a 61-year-old man with medical history of congenital hemophilia A presenting with typical clinical features of SSCNS associated with extensive hypo-intensity on fast 2D gradient-echo-weighted sequences, along the spinal cord, posterior fossa's structures and cerebral cortex. Interestingly, although his disorder was revealed by a lumbar spinal stenosis, presurgical imaging and subclinical hearing impairment preceding the surgery suggest another underlying cause. As a comprehensive work-up performed in our department ruled-out usual causes of SSCNS, this case reinforces the question of the ability for hemophilia A to generate SSCNS on its own.
Published: 2021

16. A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation

Author: Tábita Hünemeier, Andres Ruiz-Linares, Samuel Canizales-Quinteros, Christel Thauvin-Robinet, Betty Bonfante, Juan Camilo Chacón-Duque, Laurence Duplomb, Charlotte Montillot, Sagnik Palmal, Javier Mendoza-Revilla, Justin Cotney, Laurence Faivre, Seth M. Weinberg, Victor Acuña-Alonzo, Emma Wentworth, Philip H. Jones, Claudia Jaramillo, Caroline Costedoat, Morgane Dubied, David J. Balding, Manfred Kayser, Pierre Faux, Francisco Rothhammer, Mirsha Sánchez-Quinto, Carla Gallo, Paola Everardo-Martínez, Macarena Fuentes-Guajardo, Evie Stergiakouli, Pirro G. Hysi, Ziyi Xiong, Giovanni Poletti, Ceferino Varón-González, Rodrigo Barquera, Maria Cátira Bortolini, Laurence J. Howe, Lauriane Poloni, Rolando González-José, Valeria Villegas, Malena Hurtado, Kaustubh Adhikari, William Arias, Vanessa Granja, Lavinia Schuler-Faccini, Virginia Ramallo, John R. Shaffer, Timothy C. Cox, Tim D. Spector, Gabriel Bedoya, Hugo Villamil-Ramírez, Caio Cesar Silva de Cerqueira, Fan Liu, Binnaz Yalcin, Jorge Gómez-Valdés, Nicolas Navarro, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Universidad Peruana Cayetano Heredia (UPCH), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), University of Connecticut Health Center [Farmington], Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Universidad de Tarapaca, The Natural History Museum [London] (NHM), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], National School of Anthropology and History [Mexico City, Mexico] (NSAH), Max Planck Institute for the Science of Human History (MPI-SHH), Max-Planck-Gesellschaft, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Instituto Nacional de Medicina Genomica, Scientific Police of São Paulo State [Ourinhos, Brazil], Universidade de São Paulo = University of São Paulo (USP), Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Centro Nacional Patagónico (CENPAT), Beijing Genomics Institute [Shenzhen] (BGI), University of Chinese Academy of Sciences [Beijing] (UCAS), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Bristol [Bristol], King‘s College London, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Melbourne, University of Missouri [Kansas City] (UMKC), University of Missouri System, The Open University [Milton Keynes] (OU), Fudan University [Shanghai], Work leading to this publication was funded by grants from the National Natural Science Foundation of China (#31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), the Ministry of Science and Technology of China (2020YFE0201600), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) and the 111 Project (B13016), the Leverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), the Excellence Initiative of Aix-Marseille University–A*MIDEX (a French 'Investissements d’Avenir' program), Universidad de Antioquia (CODI sostenibilidad de grupos 2013-2014 and MASO 2013-2014), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Apoio a Núcleos de Excelência Program), Fundação de Aperfeiçoamento de Pessoal de Nível Superior, the National Institute of Dental and Craniofacial Research (R01-DE027023, U01-DE020078, R01-DE016148, and X01-HG007821), and a Santander Research and Scholarship Award. B.B. is supported by a doctoral scholarship from Ecole Doctorale 251 Aix-Marseille Université., ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), Biogéosciences [UMR 6282] [Dijon] (BGS), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, École pratique des hautes études (EPHE), Laboratorios de Investigación y Desarrollo (LID), Unit of Human Evolutionary Genetics, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Department of Genetics and Genome Sciences, University of Connecticut (UCONN), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and Environment, Department of Genetic Identification, Departamento de Tecnología Médica, Division of Vertebrates and Anthropology, Genética Molecular (GENMOL), Molecular Genetics Laboratory, National School of Anthropology and History, Department of Archaeogenetics [Jena] (DAG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Forensic Science, Universidad Nacional Autónoma de México (UNAM), Unidad de Genomica de Poblaciones Aplicada a la Salud, Universidad Nacional Autónoma de México (UNAM)-Instituto Nacional de Medicina Genomica, Scientific Police of São Paulo State, Departamento de Genética e Biologia Evolutiva, Universidade de São Paulo (USP), Departamento de Genética, Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS)-Instituto de Biociencias, Instituto Patagónico de Ciencias Sociales y Humanas, Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Key Laboratory of Genomic and Precision Medicine [Beijing, China], Beijing Genomics Institute [Shenzhen] (BGI)-University of Chinese Academy of Sciences [Beijing] (UCAS), Center for Craniofacial and Dental Genetics, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Department of Human Genetics, Department of Anthropology, Medical Research Council Integrative Epidemiology Unit, University of the West of England [Bristol] (UWE Bristol), School of Oral and Dental Sciences, Department of Twin Research & Genetic Epidemiology, King's College London, Facultad de Medicina & Instituto de Alta Investigacion, Universidad de Tarapaca-Universidade de Chile, Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne-University of Melbourne, Department of Oral and Craniofacial Sciences, University of Missouri System-University of Missouri System, School of Mathematics and Statistics [Milton Keynes], Faculty of Science, Technology, Engineering and Mathematics [Milton Keynes], The Open University [Milton Keynes] (OU)-The Open University [Milton Keynes] (OU), State Key Laboratory of Genetics Engineering & MOE Key Laboratory of Contemporary Anthropology, Fudan University [Shanghai]-School of Life Sciences, Work leading to this publication was funded by grantsfrom the National Natural Science Foundation of China (#31771393), the Scientific andTechnology Committee of Shanghai Municipality (18490750300), the Ministry ofScience and Technology of China (2020YFE0201600), the Shanghai Municipal Scienceand Technology Major Project (2017SHZDZX01) and the 111 Project (B13016), theLeverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), the Excellence Initiative ofAix-Marseille University–A*MIDEX (a French 'Investissements d’Avenir' program),Universidad de Antioquia (CODI sostenibilidad de grupos 2013-2014 and MASO 2013-2014), Conselho Nacional de Desenvolvimento Científico e Tecnológico,Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Apoio a Núcleos deExcelência Program), Fundação de Aperfeiçoamento de Pessoal de Nível Superior, theNational Institute of Dental and Craniofacial Research (R01-DE027023, U01-DE020078,R01-DE016148, and X01-HG007821), and a Santander Research and Scholarship Award.B.B. is supported by a doctoral scholarship from Ecole Doctorale 251 Aix-MarseilleUniversité., and Genetic Identification
Subjects: haplotype, Latin Americans, [SDV]Life Sciences [q-bio], [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Vesicular Transport Proteins, Genome-wide association study, Genome-wide association studies, Regulatory sequences, purl.org/becyt/ford/1 [https], Mice, 0302 clinical medicine, Native Americans, single nucleotide polymorphism, GWAS, 10. No inequality, Two-dimensional profiles, Research Articles, Mammals, 0303 health sciences, Multidisciplinary, biology, adult, article, SciAdv r-articles, Genomic regions, Hispanic or Latino, craniofacial development, VPS13B, GENÉTICA, Phenotype, American Indian, regulatory sequence, HUMAN POPULATION, Research Article, Morphology, Latin americans, Genotype, animal experiment, introgression, Introgression, Polymorphism, Single Nucleotide, Homo denisovan, 03 medical and health sciences, male, Animals, Humans, controlled study, human, Craniofacial, Facial feature, purl.org/becyt/ford/1.6 [https], Denisovan, Gene, mouse, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, nonhuman, genome-wide association study, Haplotype, face, Human Genetics, Single nucleotide polymorphisms, biology.organism_classification, photography, thickness, purl.org/pe-repo/ocde/ford#3.01.02 [https], facies, DENOSIVAN HAPLOTYPE, Evolutionary biology, Anthropology, Face, 030217 neurology & neurosurgery, purl.org/pe-repo/ocde/ford#1.06.07 [https], Genome-Wide Association Study
Abstract: We carried out a genome-wide association study in Latin Americans and identified novel face morphology loci.., To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.
Published: 2021

17. The case of methotrexate and the lung:Dr Jekyll and Mr Hyde

Author: Paolo Spagnolo, Mouhamad Nasser, Elisabeth Bendstrup, Claudia Valenzuela, Vincent Cottin, Martin Kolb, Philippe Bonniaud, Hospices Civils de Lyon, Hôpital Louis Pradel, Lyon, France., Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Aarhus University Hospital, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, University Hospital of Padua, Universidad Autonoma de Madrid (UAM), McMaster University [Hamilton, Ontario], ROSSI, Sabine, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), and Universidad Autónoma de Madrid (UAM)
Subjects: 030203 arthritis & rheumatology, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung, Drug discontinuation, business.industry, medicine.disease, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Increased risk, medicine.anatomical_structure, Internal medicine, medicine, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Methotrexate, 030212 general & internal medicine, business, ComputingMilieux_MISCELLANEOUS, Hypersensitivity pneumonitis, medicine.drug
Abstract: Methotrexate can induce subacute hypersensitivity pneumonitis, a potentially lethal condition that should lead to drug discontinuation; however, its use does not seem to be associated with increased risk of chronic fibrosing ILD in rheumatoid arthritishttps://bit.ly/3sCyjji
Published: 2021

18. Impact of the polycarbonate strippers used in assisted reproduction techniques on embryonic development

Author: C Naylies, Y Lippi, M Guilleman, Patricia Fauque, N. Gatimel, Véronique Gayrard, G Tavenier, A A Huesca, Jean Parinaud, Roger Leandri, Jessika Moreau, CHU Toulouse [Toulouse], Groupe de recherche en fertilité humaine ( GRFH), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), UMS006 Service d'Experimentation Animale, Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Chronic exposure, bisphenol A, [SDV]Life Sciences [q-bio], Preimplantation Embryos, Biology, Andrology, Embryo Culture Techniques, 03 medical and health sciences, 0302 clinical medicine, In vivo, Pregnancy, medicine, Humans, Blastocyst, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, Zygote, Polycarboxylate Cement, Rehabilitation, Embryogenesis, Obstetrics and Gynecology, Embryo, ARTs, Embryonic stem cell, Europe, medicine.anatomical_structure, Reproductive Medicine, polycarbonate, embryonic development, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Female, transcriptome
Abstract: STUDY QUESTION Do daily manipulations of preimplantation embryos with polycarbonate (PC)—made bisphenol A (BPA)—releasing strippers influence embryo development? SUMMARY ANSWER Compared to glass strippers, PC strippers enhance the blastocyst development rate but this does not seem to be BPA-related. WHAT IS KNOWN ALREADY PC strippers have been shown to release tiny amounts (around 0.5 ng/ml BPA) of BPA in routine human IVF procedures. A chronic exposure to BPA either in vivo or in vitro during the preimplantation period can impact post-implantation and post-natal development. BPA can act rapidly by binding to membrane receptors and inducing rapid non-genomic effects. STUDY DESIGN, SIZE, DURATION This experimental study using mouse embryos had a balanced design and blinded evaluations of the endpoints. PARTICIPANTS/MATERIALS, SETTING, METHODS In vivo fertilized zygotes were obtained from outbred Swiss CD1 mice crossings after an ovarian stimulation. The zygotes were allocated to three daily handling conditions (HCs) and cultured until Day 4 in a single human commercial medium. Each day, the embryos were handled for 20 s either in a PC stripper (HC1) or in a glass stripper (HC2). In HC3, the embryos were pre-exposed to 0.5 ng/ml BPA before being handled for 20 s in a glass stripper. Handling operations were repeated on Days 1, 2 and 3. Embryo development was assessed blindly on Day 4. Expanded blastocysts were selected for a transcriptomic analysis using Agilent Sureprint G3 Mouse GE v2 microarrays and the retrotransposon LINE1-Orf2 expression was analysed using qRT-PCR, as a proxy for a global evaluation of the epigenetic status. MAIN RESULTS AND THE ROLE OF CHANCE Compared to the embryos manipulated in HC2 (n = 243), those in HC1 (n = 228) developed significantly more often to the blastocyst stage (55 vs 46%; P LARGE SCALE DATA https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE148868. LIMITATIONS, REASONS FOR CAUTION Our results using a mouse model designed to mimic human conditions (outbred strain, human commercial IVF dishes and a unique commercial human embryonic culture media) are reassuring since no gene was found to be differentially expressed, including LINE-1 genes, as a proxy for a global evaluation of the epigenetic status. However, no global epigenetic analysis of the genome has been performed. Furthermore, we did not evaluate post-implantation events, although BPA exposure during peri-conception could affect foeto-placental and post-natal development. WIDER IMPLICATIONS OF THE FINDINGS Based on the precautionary principle, several European countries banned the use of BPA in baby bottles and food packaging several years before European Agencies took an official position. The question of applying this principle to plastics in closed contact with human embryos is raised. Further studies are needed for a decision to be made. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a grant from the Agence de Biomédecine (AOR 2016). The authors declare no competing interest.
Published: 2021

19. Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Author: Matalonga, Leslie, Hernández-Ferrer, Carles, DITF-ITHACA, Solve-RD, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cohen, Enzo, DITF-euroNMD, Solve-RD, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G, Horvath, Rita, Houlden, Henry, Johari, Mridul, Lau, Jarred, Lochmüller, Hanns, DITF-RND, Solve-RD, Macken, William L, Musacchia, Francesco, Nascimento, Andres, Natera-de Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D S, Polavarapu, Kiran, Cruz, Pedro M Rodriguez, Tonda, Raul, Sarkozy, Anna, Savarese, Marco, Selvatici, Rita, Thompson, Rachel, Udd, Bjarne, Van de Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Balicza, Peter, Laurie, Steven, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Fernandez-Callejo, Marcos, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Schüle-Freyer, Rebecca, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, Picó, Daniel, van de Warrenburg, Bart, van Os, Nienke, Wayand, Melanie, Wilke, Carlo, Haack, Tobias B, Graessner, Holm, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Garcia-Linares, Carles, Sturm, Marc, Schulze-Hentrich, Julia M, Kessler, Christoph, Heutink, Peter, Brunner, Han, Scheffer, Hans, Papakonstantinou, Anastasios, Hoogerbrugge, Nicoline, 't Hoen, Peter A C, Steyaert, Wouter, Sablauskas, Karolis, Te Paske, Iris, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Corvó, Alberto, Brookes, Anthony J, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Piscia, Davide, Joshi, Ricky, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Duffourd, Yannis, Tisserant, Emilie, Diez, Hector, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Bullich, Gemma, Gut, Ivo, Corvo, Alberto, Garcia, Carles, Hernández, Carles, Paramonov, Ida, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hoischen, Alexander, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Consortia, Solve-RD, Spalding, Dylan, Senf, Alexander, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, de Jonghe, Peter, Banfi, Sandro, Torella, Annalaura, Cuesta, Isabel, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A, Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B, group, Solve-RD SNV-indel working, Denommé-Pichon, Anne-Sophie, Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F Javier Alonso García, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Gilissen, Christian, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Beeson, David, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Li, Shuang, Prasanth, Sivakumar, Robinson, Peter, van der Velde, Joeri K, de Voer, Richarda M, Evans, Gareth, Sommer, Anna Katharina, Töpf, Ana, Paske, Iris Te, Tischkowitz, Marc, Casari, Giorgio, Ciolfi, Andrea, Dallapiccola, Bruno, de Boer, Elke, Vissers, Lisenka E L M, Hammarsjö, Anna, Havlovicova, Marketa, Hugon, Anne, de Voer, Richarda, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, DITF-GENTURIS, Solve-RD, Posada, Manuel, Ryba, Lukas, Schwarz, Martin, Trimouille, Aurélien, Solve RD SNV Indel Working Grp, Solve RD DITF GENTURIS, Solve RD DITF ITHACA, Solve RD DITF-euroNMD, Solve RD DITF RND, Solve RD Consortia, Matalonga, L., Hernandez-Ferrer, C., Piscia, D., Cohen, E., Cuesta, I., Danis, D., Denomme-Pichon, A. -S., Duffourd, Y., Gilissen, C., Johari, M., Laurie, S., Li, S., Nelson, I., Peters, S., Paramonov, I., Prasanth, S., Robinson, P., Sablauskas, K., Savarese, M., Steyaert, W., van der Velde, J. K., Vitobello, A., Schule, R., Synofzik, M., Topf, A., Vissers, L. E. L. M., de Voer, R., Aretz, S., Capella, G., de Voer, R. M., Evans, G., Pelaez, J. G., Holinski-Feder, E., Hoogerbrugge, N., Laner, A., Oliveira, C., Rump, A., Schrock, E., Sommer, A. K., Steinke-Lange, V., Paske, I., Tischkowitz, M., Valle, L., Banka, S., Benetti, E., Casari, G., Ciolfi, A., Clayton-Smith, J., Dallapiccola, B., de Boer, E., Ellwanger, K., Faivre, L., Graessner, H., Haack, T. B., Hammarsjo, A., Havlovicova, M., Hoischen, A., Hugon, A., Jackson, A., Kleefstra, T., Lindstrand, A., Lopez-Martin, E., Macek, M., Morleo, M., Nigro, V., Nordgren, A., Pettersson, M., Pinelli, M., Pizzi, S., Posada, M., Radio, F. C., Renieri, A., Rooryck, C., Ryba, L., Schwarz, M., Tartaglia, M., Thauvin, C., Torella, A., Trimouille, A., Verloes, A., Vissers, L., Votypka, P., Vyshka, K., Zurek, B., Baets, J., Beijer, D., Bonne, G., Cossins, J., Evangelista, T., Ferlini, A., Hackman, P., Hanna, M. G., Horvath, R., Houlden, H., Lau, J., Lochmuller, H., Macken, W. L., Musacchia, F., Nascimento, A., Natera-de Benito, D., Piluso, G., Pini, V., Pitceathly, R. D. S., Polavarapu, K., Cruz, P. M. R., Sarkozy, A., Selvatici, R., Thompson, R., Udd, B., Van de Vondel, L., Vandrovcova, J., Zaharieva, I., Balicza, P., Chinnery, P., Durr, A., Haack, T., Hengel, H., Kamsteeg, E. -J., Kamsteeg, C., Lohmann, K., Macaya, A., Marce-Grau, A., Maver, A., Molnar, J., Munchau, A., Peterlin, B., Riess, O., Schols, L., Schule-Freyer, R., Stevanin, G., Timmerman, V., van de Warrenburg, B., van Os, N., Wayand, M., Wilke, C., Tonda, R., Fernandez-Callejo, M., Pico, D., Garcia-Linares, C., Papakonstantinou, A., Corvo, A., Joshi, R., Diez, H., Gut, I., Beltran, S., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Kessler, C., Heutink, P., Brunner, H., Scheffer, H., 't Hoen, P. A. C., te Paske, I., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Alexander, E., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Bullich, G., Garcia, C., Hernandez, C., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Allamand, V., Yaou, R. B., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Kremlik, V., Parkinson, H., Keane, T., Spalding, D., Senf, A., Robert, G., Costa, A., Patch, C., Hanna, M., Reilly, M., Muntoni, F., de Jonghe, P., Banfi, S., Rossi, R., Neri, M., Spier, I., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Castello, R., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Molnar, M. J., Herzog, R., Pauly, M., Osorio, A. N., de Benito, D. N., Beeson, D., Unión Europea. Comisión Europea. H2020, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), Government of Catalonia (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto Nacional de Bioinformatica (España), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Instituto de Salud Carlos III [Madrid] (ISC), Radboud University Medical Center [Nijmegen], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Barcelona Institute of Science and Technology (BIST), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Folkhälsan Research Center, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Myologie, University of Helsinki, Department of Medical and Clinical Genetics, Medicum, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Genetic testing, Computer science, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], EXOME, MEDICAL GENETICS, Diseases, Disease, VARIANTS, Genome informatics, Genomic analysis, Diseases, Genetic testing, Genome informatics, Genomic analysis, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Genetics (clinical), Exome sequencing, 0303 health sciences, Application programming interface, methods [Genomics], 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Pedigree, diagnosis [Rare Diseases], Chemistry, Medical genetics, medicine.medical_specialty, methods [Genetic Testing], MEDLINE, Socio-culturale, Phenome, AMERICAN-COLLEGE, INHERITANCE, Sensitivity and Specificity, Article, standards [Genetic Testing], 03 medical and health sciences, Rare Diseases, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetics, medicine, Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Data science, Workflow, 3111 Biomedicine, standards [Genomics], Human medicine, Software
Abstract: Correction to: Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. Eur J Hum Genet. 2021 Sep;29(9):1466-1469. doi: 10.1038/s41431-021-00934-6. PMID: 34393220 Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. We also acknowledge the support of the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement and the Co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. Sí
Published: 2021

20. PURA- Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum

Author: Dario Pruna, Theresa Grebe, Felippe Borlot, Michael J. Esser, Juan Pablo Appendino, Katherine L. Helbig, Elisa Ballardini, Casey Brew, Anne-Sophie Denommé-Pichon, Anne Ronan, Laurie A. Demmer, Usha Kini, Marta Somorai, Julie Vogt, Sébastien Moutton, Raffaella Faggioli, Julien Van-Gils, Davide Ognibene, Sara Olivotto, Sabine Grønborg, David Coman, David P. Bick, Guido Rubboli, Orrin Devinsky, Atiya S. Khan, Robyn Whitney, Christine Coubes, Caroline Nava, Karen Keough, SakkuBai R. Naidu, Lucio Giordano, Davide Colavito, Dominic Spadafore, Arnaud Isapof, Walla Al-Hertani, Antonio Vitobello, Andrea V. Andrade, Gaetano Cantalupo, Sandra Whalen, Boudewijn Gunning, Shanawaz Hussain, David Hunt, Nathan Noble, Bertrand Isidor, Beatriz Gamboni, Katrine M Johannesen, Julien Buratti, Stephanie Moortgat, Ida Cursio, Agnese Suppiej, Delphine Héron, Lía Mayorga, William Benko, Rahul Raman Singh, Cyril Mignot, Sotirios Keros, Aurore Garde, Nicola Foulds, Claudia A. L. Ruivenkamp, Elena Gardella, Barbara Scelsa, Fernanda Góes, Laurence Faivre, Richard J. Leventer, Ashley Collier, Farha Tokarz, Thomas Courtin, Klaas J. Wierenga, Xilma R. Ortiz-Gonzalez, Frédéric Tran-Mau-Them, Alejandra Mampel, Lynn Greenhalgh, Ashlea Franques, Amélie Piton, Felicia Varsalone, Marjolaine Willems, Alessandro Orsini, Diana Rodriguez, Clothilde Ormieres, Helen Stewart, Boris Keren, Austin Larson, Cathrine E. Gjerulfsen, Julie S. Cohen, Margot R.F. Reijnders, Mel Anderson, Shailesh Asakar, Rikke S. Møller, Alice Bonuccelli, Alexandra Afenjar, Claudio Graziano, Elaine Wirrell, Simona Damioli, Sangeetha Yoganathan, Devorah Segal, Ingo Helbig, Mindy H. Li, Rob P.W. Rouhl, Sarah Hicks, Allan Bayat, Holly Dubbs, Stefania Bigoni, Kelly Ratke, John Brandsema, Eva H. Brilstra, univOAK, Archive ouverte, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Southern Denmark (SDU), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mayo Clinic [Jacksonville], Département de pédiatrie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), and University of Colorado Anschutz [Aurora]
Subjects: Pediatrics, medicine.medical_specialty, Socio-culturale, [SDV.GEN] Life Sciences [q-bio]/Genetics, Electroencephalography, Epilepsy, Developmental and Epileptic Encephalopathy, Intellectual disability, medicine, Genetics (clinical), feeding difficulties, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.diagnostic_test, business.industry, fungi, medicine.disease, Hypotonia, Epileptic spasms, Neonatal hypotonia, neonatal hypotonia, Epilepsy syndromes, Cohort, epilepsy, Neurology (clinical), medicine.symptom, business
Abstract: Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.
Published: 2021

21. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author: Anne Miret, Lola Lemasson, Benjamin Cogné, Laurence Perrin, Frédéric Tran Mau-Them, Rémi Mathevet, Marion Boucon, Elise Schaefer, Christel Thauvin-Robinet, Christine Juif, Juliette Piard, Solène Bourgouin, Jenny Cornaton, Bertrand Isidor, Catherine Sarret, Fabienne Prieur, Coralie Gonin-Olympiade, Alexandra Afenjar, Christine Coubes, Boris Keren, Bénédicte Gérard, Catherine Vincent-Delorme, Kim Giraudat, Laurence Faivre, Amélie Piton, Antonio Vitobello, Thomas Smol, Annick Toutain, Arthur Sorlin, Sylvie Odent, Yann Trousselet, Fanny Tessier, Martin Chevarin, David Geneviève, Sébastien Moutton, Anne-Claire Gelineau, Ange-Line Bruel, Claire Nicolas, Aurore Garde, Philippe Khau-Van-Kien, Christophe Philippe, Solveig Heide, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Etienne, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, [SDV]Life Sciences [q-bio], Neurocognitive Disorders, Transposases, Neuropsychological Tests, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, [SCCO]Cognitive science, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Global developmental delay, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Dysexecutive syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Neuropsychology, Genetic Variation, medicine.disease, 3. Good health, Developmental disorder, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Mutation, Autism, Female, France, business, Neurocognitive
Abstract: White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.
Published: 2020

22. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Author: Katharina Steindl, Alain Verloes, Cornelia Kraus, Rachel Fisher, Katrin Õunap, Amber Begtrup, Steffen Syrbe, Theresa Brunet, Antonio Vitobello, Laurence Faivre, Reza Asadollahi, Jessica Becker, Maja Hempel, Dave A Dyment, Christiane Zweier, John H McDermott, Bernt Popp, Elaine Suk-Ying Goh, Lynette G. Sadleir, Anaïs Begemann, Siddharth Banka, Gwenaël Le Guyader, Elisabeth Schuler, Anne-Sophie Denommé-Pichon, Kathleen Brown, Gaetan Lesca, Frédéric Tran Mau-Them, Lucia Ribeiro Machado Haertel, Maryline Carneiro, Amelie Theresa Van der Ven, Markus Zweier, Hartmut Engels, Heinrich Sticht, Theresia Herget, Jessika Johannsen, Bader Alhaddad, Nadine N. Hauer, Robert C. Day, Tiia Reimand, M. J. Hajianpour, Manuel Schiff, Kirsty McWalter, Margarita Saenz, Tatjana Bierhals, Pierre Meyer, Ange-Line Bruel, Martina Russo, Korbinian M. Riedhammer, Kirsten Cremer, Anita Rauch, Marjolaine Willems, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Robert Debré
Subjects: 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, WAVEregulatory complex (WRC), 030105 genetics & heredity, Biology, Article, Intellectual disability, Epilepsy, CYFIP2, WAVE-regulatory complex (WRC), WASF, 03 medical and health sciences, Neurodevelopmental disorder, Seizures, medicine, Missense mutation, Humans, Genetics(clinical), Gene, Genetics (clinical), Actin, Adaptor Proteins, Signal Transducing, Genetics, medicine.disease, Actin cytoskeleton, Phenotype, Hypotonia, Actins, 3. Good health, ddc, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neurodevelopmental Disorders, intellectual disability, epilepsy, medicine.symptom
Abstract: International audience; Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype–phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts.Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
Published: 2020

23. Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation

Author: Da Costa, Romain, De Almeida, Steven, Chevarin, Martin, Hadj-Rabia, Smail, Leclerc-Mercier, Stéphanie, Thauvin-Robinet, Christel, Garrido, Carmen, Faivre, Laurence, Vabres, Pierre, Duplomb, Laurence, Jego, Gaëtan, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe HSPpathies (LNC - U1231), and Service de Dermatologie (CHU de Dijon)
Subjects: [SDV]Life Sciences [q-bio]
Published: 2020

24. Extracellular vesicles from myelodysplastic mesenchymal stromal cells induce DNA damage and mutagenesis of hematopoietic stem cells through miRNA transfer

Author: Rémy Sadoul, Mathieu Meunier, Karine Laulagnier, Jean-Paul Issartel, Sylvie Tondeur, Sophie Park, Claire Jouzier, Quentin Testard, Audrey Guttin, Christine Lefebvre, Sarah Ancelet, Christine Chatellard, Julien Thevenon, Pierre Hainaut, Virginie Persoons, Benoît Polack, Johanna Zannoni, Jean-François Deleuze, Jean-Yves Cahn, Florent Chuffart, Mylène Pezet, Sophie Rousseaux, David Laurin, Karin Pernet-Gallay, University Clinic of Hematology, Centre Hospitalier Universitaire [Grenoble] (CHU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), PDC*line Pharma SAS, Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), and CHU Grenoble
Subjects: Ribonuclease III, Cancer Research, DNA damage, [SDV]Life Sciences [q-bio], Extracellular vesicles, DEAD-box RNA Helicases, Extracellular Vesicles, microRNA, Humans, Chemistry, Mesenchymal stem cell, Mutagenesis, Mesenchymal Stem Cells, Hematology, Hematopoietic Stem Cells, Microenvironement tumoral, Cell biology, MicroRNAs, Haematopoiesis, Mesenchymal Stem Cell, Oncology, Myelodysplastic Syndromes, Stem cell, Myelodysplastic syndrome, DNA Damage
Abstract: International audience; Physiopathology of myelodysplastic syndrome (MDS) remains poorly understood and the role of the microenvironment is increasingly highlighted. Recent studies in mouse models demonstrate that abnormalities of mesenchymal stromal cells (MSC) contribute to the physiopathology of MDS. In particular, genetic deletion of dicer1, a gene encoding a type III RNase essential for the genesis of miRNA, in murine MSC-derived osteoprogenitors led to a pathological microenvironment generating myelodysplastic features in hematopoietic progenitors and ultimately leading to acute myeloid leukemia [1]. In human, there is an increased susceptibility to senescence of the MDS mesenchymal stem cells and defects in the support properties of the growth of hematopoietic stem cells (HSC) [2]. These observations establish a causal relationship between deregulation of the hematopoietic niche and MDS pathogenesis. However, so far only few studies have addressed the mechanisms by microenvironmental MSC and HSC exchange signals that may interfere with miRNA processing, specifically in the human MDS microenvironment.
Published: 2020

25. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Author: Tania Attié-Bitach, Philippe Jonveaux, Alice Goldenberg, Antonio Vitobello, Nicole Laurent, Marjolaine Willems, Valérie Kremer, Dominique Gaillard, Chloé Quélin, Sebastien Moutton, Marion Aubert-Lenoir, Yannis Duffourd, Anne-Sophie Lebre, Anne-Claire Brehin, James Lespinasse, Yline Capri, Nolwenn Jean-Marçais, Maria Cristina Antal, Frédéric Tran Mau-Them, Nathalie Marle, Daphné Lehalle, Nicolas Bourgon, Sophie Blesson, Bernard Foliguet, Laetita Lambert, Nicole Bigi, Mélanie Fradin, Emilie Tisserant, Christel Thauvin-Robinet, Ange-Line Bruel, Elisabeth Alanio, Marie-Hélène Saint-Frison, Christine Francannet, Anne-Marie Guerrot, Paul Kuentz, Elise Schaefer, Anne-Marie Beaufrere, Sylvie Odent, Francine Arbez-Gindre, Laurence Faivre, Christophe Philippe, Julien Thevenon, Sophie Patrier-Sallebert, Nada Houcinat, Celine Poirisier, Sophie Nambot, Mathilde Lefebvre, Mirna Assoum, Françoise Girard-Lemaitre, Sophie Collardeau-Frachon, Marie-José Perez, Jean-Louis Mandel, Jean-Pierre Mazutti, Renaud Touraine, Philippe Loget, Salima El Chehadeh, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), European Organization for Nuclear Research (CERN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Métropole Savoie [Chambéry], CHU Saint-Etienne, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire [Grenoble] (CHU), CarMeN, laboratoire, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 14-013 FOETEX, Interregional French PHRC, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Candidate gene, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Biology, Congenital Abnormalities, Cohort Studies, complex traits, 03 medical and health sciences, Fetus, Molecular genetics, medicine, Humans, Abnormalities, Multiple, Exome, Clinical significance, genetics, Gene, Genetic Association Studies, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, 030305 genetics & heredity, Sequence Analysis, DNA, Phenotype, [SDV] Life Sciences [q-bio], molecular genetics, reproductive medicine
Abstract: PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.
Published: 2020

26. NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients

Author: Laurence Perrin, Silvia Cappello, Francesco Neri, Arthur Sorlin, Philippe Khau Van Kien, Ludovico D'Incerti, Françoise Devillard, Rossella Di Giaimo, Paul Kuentz, Agnès Loubat, Marjolaine Willems, Laurence Faivre, Frédéric Tran Mau-Them, Salvatore Oliviero, Michèle Studer, Anna Lisa Romano, Christophe Philippe, Michele Bertacchi, Carolina Frassoni, Aurore Garde, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Robert Debré Paris, Hôpital Robert Debré, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique biologique histologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Université de Naples, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Bertacchi, Michele, Romano, Anna Lisa, Loubat, Agnè, Tran Mau-Them, Frederic, Willems, Marjolaine, Faivre, Laurence, Khau van Kien, Philippe, Perrin, Laurence, Devillard, Françoise, Sorlin, Arthur, Kuentz, Paul, Philippe, Christophe, Garde, Aurore, Neri, Francesco, Di Giaimo, Rossella, Oliviero, Salvatore, Cappello, Silvia, D'Incerti, Ludovico, Frassoni, Carolina, and Studer, Michèle
Subjects: cell cycle dynamics, PAX6 Transcription Factor, [SDV]Life Sciences [q-bio], cell cycle dynamic, Neocortex, Biology, Regenerative Medicine, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Neural Stem Cells, Optic Atrophies, Hereditary, Parietal Lobe, Cortex (anatomy), BBSOAS, medicine, Animals, Humans, Molecular Biology, Gyrification, 030304 developmental biology, 0303 health sciences, COUP Transcription Factor I, General Immunology and Microbiology, General Neuroscience, Neurogenesis, Articles, Human brain, NR2F1/COUP-TFI, cortical folding, medicine.disease, Disease Models, Animal, neurodevelopmental disease, medicine.anatomical_structure, NR2F1/COUP‐TFI, Occipital Lobe, PAX6, Haploinsufficiency, Development & Differentiation, Neuroscience, 030217 neurology & neurosurgery
Abstract: The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra‐Bosch‐Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss‐of‐function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria‐like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long‐term self‐renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area‐specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification., Reduced levels of the neuronal differentiation factor NR2F1/COUP‐TFI impairs brain cortex folding in humans, and disrupts regional neural progenitor dynamics in the neocortex of a BBSOAS disease mouse model.
Published: 2020

27. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome

Author: Gerarda Cappuccio, Camille Sayou, Pauline Le Tanno, Emilie Tisserant, Ange-Line Bruel, Sara El Kennani, Joaquim Sá, Karen J. Low, Cristina Dias, Markéta Havlovicová, Miroslava Hančárová, Evan E. Eichler, Françoise Devillard, Sébastien Moutton, Julien Van-Gils, Christèle Dubourg, Sylvie Odent, Bénédicte Gerard, Amélie Piton, Toshiyuki Yamamoto, Nobuhiko Okamoto, Helen Firth, Kay Metcalfe, Anna Moh, Kimberly A. Chapman, Erfan Aref-Eshghi, Jennifer Kerkhof, Annalaura Torella, Vincenzo Nigro, Laurence Perrin, Juliette Piard, Gwenaël Le Guyader, Thibaud Jouan, Christel Thauvin-Robinet, Yannis Duffourd, Jaya K. George-Abraham, Catherine A. Buchanan, Denise Williams, Usha Kini, Kate Wilson, Nicola Brunetti-Pierri, Giorgio Casari, Michele Pinelli, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Valeria Capra, Giancarlo Parenti, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Sandro Banfi, Marcella Zollino, Mario Montomoli, Donatelli Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, Claudia Santoro, Angela Peron, Chiara Pantaleoni, Raffaele Castello, Stefano D’Arrigo, Sérgio B. Sousa, Raoul C.M. Hennekam, Bekim Sadikovic, Julien Thevenon, Jérôme Govin, Antonio Vitobello, Università degli studi di Napoli Federico II, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Motol [Prague], University of Washington [Seattle], Centre Hospitalier Universitaire [Grenoble] (CHU), Université de Bordeaux (UB), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), London Health Sciences Center (LHSC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), GSP15001, Fondazione Telethon, 209568/Z/17/Z, Wellcome Trust, Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, M., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., University of Naples Federico II = Università degli studi di Napoli Federico II, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, General Paediatrics, APH - Quality of Care, and Brunetti-Pierri, Nicola
Subjects: Foot Deformities, Foot Deformities, Congenital, [SDV]Life Sciences [q-bio], Biology, Blepharophimosis, Settore MED/03 - GENETICA MEDICA, Hypotrichosis, Chromatin remodeling, 03 medical and health sciences, Congenital, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, SMARCA2, medicine, Humans, Gene, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, BIS, Facies, medicine.disease, Phenotype, neurodevelopmental disorder, Nicolaides–Baraitser syndrome, intellectual disability, DNA methylation, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.
Published: 2020

28. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author: Julien Van-Gils, Kyoko Takano, Victor P. Pedro, Lauren Brick, Pascale Saugier-Veber, Tugce B. Balci, Antonio Vitobello, Marielle Alders, Justine Rousseau, Frédéric Laumonnier, Christel Thauvin-Robinet, Raoul C.M. Hennekam, Tjitske Kleefstra, Matt Tedder, Jennifer Kerkhof, Damien Sanlaville, Gaël Nicolas, François Lecoquierre, Delphine Héron, Hanxin Lin, Sophie Rondeau, Mariya Kozenko, Simone Pizzi, Alexandra Afenjar, Victoria Mok Siu, Christèle Dubourg, David Geneviève, Erfan Aref-Eshghi, Solveig Heide, Barbara R. DuPont, Peter Ainsworth, David I. Rodenhiser, Boris Keren, Nicole de Leeuw, Sandra Whalen, Martine Raynaud, Damien Ulveling, Nathalie Ruiz-Pallares, Valérie Cormier-Daire, Mouna Barat-Houari, Michael A. Levy, Roger E. Stevenson, Jennifer A. Lee, Steven A. Skinner, Alan Graham Stuart, Laurence Faivre, Marie Shaw, Gaetan Lesca, Peter Henneman, Thierry Bienvenu, Marco Tartaglia, Charles E. Schwartz, Andrea Ciolfi, Michael J. Friez, Michael Field, Mike Kadour, Guillaume Velasco, Jozef Gecz, Claire Francastel, Didier Lacombe, Philippe M. Campeau, Jean-Christophe Andrau, Bekim Sadikovic, Marcel M.A.M. Mannens, Jennifer Masters, Cyril Mignot, Patricia Fergelot, Nicolas Chatron, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, General Paediatrics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Quality of Care, London Health Sciences Center (LHSC), Schulich School of Medicine and Dentistry, University of Western Ontario (UWO), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Bordeaux (UB), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Medical Center [Amsterdam], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases [IRCSS San Raffaele Scientific Institute, Milan], IRCCS San Raffaele Scientific Institute [Milan, Italie], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Sainte Justine [Montréal], McMaster University [Hamilton, Ontario], University of Tasmania [Hobart, Australia] (UTAS), Shinshu University Hospital, Radboud University Medical Center [Nijmegen], Hunter Genetics, University of Notre Dame [Indiana] (UND), University of South Australia [Adelaide], The Greenwood Genetic Center, Greenwood Genetic Center [Greenwood, South Carolina, USA], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Amsterdam Reproduction and Development Institute, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre épigénétique et destin cellulaire (EDC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Computational biology, 030105 genetics & heredity, Biology, Pediatrics, Article, Cohort Studies, molecular diagnostics, 03 medical and health sciences, symbols.namesake, Genetic Heterogeneity, Gene duplication, Genetics, Humans, Hunter-McAlpine syndrome, Genetics (clinical), Mass screening, 030304 developmental biology, EpiSign, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DNA methylation, Genetic heterogeneity, 030305 genetics & heredity, Correction, Syndrome, DNA Methylation, Molecular diagnostics, Phenotype, Penetrance, Human genetics, 3. Good health, episignature, genomic DNA, 030104 developmental biology, Neurodevelopmental Disorders, uncertain clinical cases, Mendelian inheritance, symbols, Identification (biology), VUS classification
Abstract: Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access) Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.
Published: 2020

29. Author Correction: Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome [Correction to: Nature Genetics https://doi.org/10.1038/s41588-019-0498-4, published online 30 September 2019]

Author: Vabres, Pierre, Sorlin, Arthur, Kholmanskikh, Stanislav S., Demeer, Bénédicte, St Onge, Judith, Duffourd, Yannis, Kuentz, Paul, Courcet, Jean-Benoît, Carmignac, Virginie, Garret, Philippine, Bessis, Didier, Boute, Odile, Bron, Alain, Captier, Guillaume, Carmi, Esther, Devauchelle, Bernard, Genevieve, David, Gondry Jouet, Catherine, Guibaud, Laurent, Lafon, Arnaud, Mathieu Dramard, Michèle, Thévenon, Julien, Dobyns, William B., Bernard, Geneviève, Polubothu, Satyamaanasa, Faravelli, Francesca, Kinsler, Veronica A., Thauvin, Christel, Faivre, Laurence, Ross, M. Elizabeth, Rivière, Jean-Baptiste, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Weill Cornell Medicine, CHU Amiens-Picardie, McGill University = Université McGill [Montréal, Canada], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), Dermatology Office, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Seattle Children’s Research Institute, Montreal Children’s Hospital, University College of London [London] (UCL), and ProdInra, Migration
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract: Indexation en cours. In the version of this article initially published, support from the Wellcome Trust and NIHR to author Veronica A. Kinsler was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.; International audience; An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020

30. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20

Author: Anne-Sophie Denommé-Pichon, Laetitia Gouas, Martin Chevarin, Marlène Rio, Elodie Gautier, Sonia Bouquillon, Nolwenn Jean-Marçais, Jennifer Fabre-Teste, Dominique Martin, Elise Schaefer, Fabienne Giuliano, Didier Lacombe, Sophie Nambot, Gaëlle Vieville, Sophie Blesson, Paul Kuentz, Christine Francannet, Yannis Duffourd, Aurélien Juven, Alice Masurel, Patrick Callier, Arnold Munnich, Salima El Chehadeh, Sophie Rondeau, Christophe Philippe, Amélie Piton, Fanny Laffargue, Catherine Vincent Delorme, Marie Vincent, Olivier Pichon, Bénédicte Gérard, Anne-Laure Mosca-Boidron, Bertrand Isidor, Christel Thauvin-Robinet, Laurence Perrin-Sabourin, Nathalie Marle, Cédric Le Caignec, Laurence Faivre, Hubert Journel, Klaus Dieterich, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de cytogénétique (CHU de Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique-Hôpitaux de Paris, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Génétique Médicale, Hôpital Civil, Strasbourg, DGA Maîtrise de l'information (DGA.MI), Direction générale de l'Armement (DGA), Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Hôpital l'Archet, Service de Génétique Médicale, Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), FHU TRANSLAD (CHU de Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut cellule souche et cerveau (SBRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Adolescent, Hearing loss, [SDV]Life Sciences [q-bio], Mutation, Missense, Nerve Tissue Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioinformatics, Article, Corpus Callosum, 03 medical and health sciences, Ectopic calcification, Ptosis, Intellectual Disability, Genetics, Medicine, Missense mutation, Humans, Abnormalities, Multiple, Child, Ear Diseases, Wasting, Genetics (clinical), Muscle contracture, 0303 health sciences, business.industry, 030305 genetics & heredity, Macrocephaly, Calcinosis, medicine.disease, Primrose syndrome, Muscular Atrophy, Phenotype, Child, Preschool, Chromosomes, Human, Pair 3, medicine.symptom, Chromosome Deletion, business, Transcription Factors
Abstract: International audience; Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.
Published: 2020

31. Genome sequencing in cytogenetics: Comparison of short‐read and linked‐read approaches for germline structural variant detection and characterization

Author: Uguen, Kévin, Jubin, Claire, Duffourd, Yannis, Bardel, Claire, Malan, Valérie, Dupont, Jean‐Michel, El Khattabi, Laila, Chatron, Nicolas, Vitobello, Antonio, Rollat‐Farnier, Pierre‐Antoine, Baulard, Céline, Lelorch, Marc, Leduc, Aurelie, Tisserant, Emilie, Tran Mau‐Them, Frédéric, Danjean, Vincent, Délépine, Marc, Till, Marianne, Meyer, Vincent, LYONNET, Stanislas, Mosca‐Boidron, Anne‐laure, Thevenon, Julien, Faivre, Laurence, Thauvin‐Robinet, Christel, Schluth‐Bolard, Caroline, Boland, Anne, Olaso, Robert, Callier, Patrick, Romana, Serge, Deleuze, Jean‐François, Sanlaville, Damien, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Albert Trillat [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Performance analysis and optimization of LARge Infrastructures and Systems (POLARIS), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'Informatique de Grenoble (LIG), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Pôle Couple-Enfant, Département de Génétique et Procréation, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Eco-Anthropologie et Ethnobiologie (EAE), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Interactions Arbres-Microorganismes (IAM), Université de Lorraine (UL)-Institut National de la Recherche Agronomique (INRA), Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Laboratoire Information, Milieux, Médias, Médiations - EA 3820 (I3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Université de Toulon (UTLN), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service d'Histologie-Embryologie et Cytogénétique Assistance Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: Whole Genome Sequencing, lcsh:QH426-470, Method, structural variants, Chromosome Disorders, bioinformatics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], genome sequencing, Cytogenetics, lcsh:Genetics, 10X Genomics: Illumina, Intellectual Disability, Genomic Structural Variation, Humans, Abnormalities, Multiple, Genetic Testing, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS
Abstract: Background Structural variants (SVs) include copy number variants (CNVs) and apparently balanced chromosomal rearrangements (ABCRs). Genome sequencing (GS) enables SV detection at base‐pair resolution, but the use of short‐read sequencing is limited by repetitive sequences, and long‐read approaches are not yet validated for diagnosis. Recently, 10X Genomics proposed Chromium, a technology providing linked‐reads to reconstruct long DNA fragments and which could represent a good alternative. No study has compared short‐read to linked‐read technologies to detect SVs in a constitutional diagnostic setting yet. The aim of this work was to determine whether the 10X Genomics technology enables better detection and comprehension of SVs than short‐read WGS. Methods We included 13 patients carrying various SVs. Whole genome analyses were performed using paired‐end HiSeq X sequencing with (linked‐read strategy) or without (short‐read strategy) Chromium library preparation. Two different bioinformatic pipelines were used: Variants are called using BreakDancer for short‐read strategy and LongRanger for long‐read strategy. Variant interpretations were first blinded. Results The short‐read strategy allowed diagnosis of known SV in 10/13 patients. After unblinding, the linked‐read strategy identified 10/13 SVs, including one (patient 7) missed by the short‐read strategy. Conclusion In conclusion, regarding the results of this study, 10X Genomics solution did not improve the detection and characterization of SV., We compared linked‐read and short‐read sequencing in patients with structural variants. We conclude that linked‐read strategy did not improve the detection and characterization of structural variants.
Published: 2020

32. A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis

Author: Dominique Bonneau, Bruno Delobel, Catherine Boileau, Guillaume Jondeau, Christine Coubes, Jean-Luc Alessandri, Laurence Faivre, V. Carmignac, Sylvie Odent, Pauline Arnaud, Christel Thauvin-Robinet, Nadine Hanna, Caroline Racine, Carine Le Goff, Julien Thevenon, Laurent Gouya, Jill Clayton-Smith, Sophie Dupuis-Girod, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Université de Paris, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Grenoble, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Manchester [Manchester], Hôpital Lapeyronie [Montpellier] (CHU), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Hospices Civils de Lyon (HCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Burgundy Regional Council through the Plan d'Actions Regional pour l'Innovation (PARI 2015), European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs, Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, Proband, Marfan syndrome, Connective Tissue Disorder, Adolescent, [SDV]Life Sciences [q-bio], Context (language use), Biology, Marfan Syndrome, Craniosynostoses, 03 medical and health sciences, Proto-Oncogene Proteins, Intellectual disability, Genetics, medicine, Humans, Pathology, Molecular, Craniofacial, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, Marfanoid, Middle Aged, medicine.disease, Human genetics, 3. Good health, DNA-Binding Proteins, Arachnodactyly, Child, Preschool, Mutation, Female
Abstract: International audience; SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
Published: 2020

33. The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author: Amy McTague, Siddharth Srivastava, Tamison Jewett, Ali Al-Beshri, Constance Smith-Hicks, Shelagh Joss, Jennifer A. Sullivan, Sarju G. Mehta, Koenraad Devriendt, Pascal Joset, Laurence Faivre, Emma Kivuva, William G. Wilson, Gunnar Houge, Naama Orenstein, Yana Hoorne, Vickie L. Hannig, Malou Heijligers, Bart Loeys, Vandana Shashi, Katrina Prescott, Iris Verbinnen, Annick Toutain, Lauren M. Baldwin, Stephen P. Fulton, Katharina Steindl, Anne Marie Childs, Anna Chassevent, Shelley Towner, Cornelia Daumer-Haas, Oded Wechsberg, Alison Male, Hannah F. Johnson, Wendy K. Chung, Anita Rauch, Anna Ruiz, Isabelle Maystadt, Sara Reynhout, Sébastien Moutton, Yvette van Ierland, Veerle Janssens, Frédéric Laumonnier, Martina Baethmann, Lisa Lenaerts, Vani Jain, Vinod Varghese, Suzanne M. Koudijs, Elisabeth Gabau, Frédérique Bonnet-Brilhault, Rizwan Hamid, Susan E. Holder, Barbara Plecko, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Queen Elizabeth University Hospital (Glasgow), Kennedy Krieger Institute [Baltimore], University of Antwerp (UA), Universität Zürich [Zürich] = University of Zurich (UZH), Addenbrooke’s Hospital [Cambridge, UK], Columbia University Medical Center (CUMC), Columbia University [New York], North West Thames Regional Genetics Service [London, UK] (Harrow), North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow-Northwick Park Hospital [Harrow, UK] (NPH), Wake Forest University, University of Virginia [Charlottesville], Boston Children's Hospital, Prenatal Medicine Munich [Munich, Germany] (PMM), Klinikum Dritter Orden [Munich], Universitat Autònoma de Barcelona (UAB), University Hospital of Wales [Cardiff, UK], University of Alabama at Birmingham [ Birmingham] (UAB), Le Bonheur Children's Hospital [Memphis, TN, USA] (LBCH), Schneider Children’s Medical Center of Israel [Petah Tikva], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Leeds Teaching Hospitals NHS Trust, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Duke University Medical Center, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Royal Devon and Exeter NHS Foundation Trust [UK], Great Ormond Street Institute of Child Health [London, UK] (UCL), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University Graz, Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Haukeland University Hospital, University of Bergen (UiB), Leuven Brain Institute [Leuven, Belgium] (LBI), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Clinical Genetics, University of Virginia, University Hospital of Wales (UHW), Tel Aviv University (TAU), Great Ormond Street Institute of Child Health (UCL), and Laumonnier, Frédéric
Subjects: 0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Intellectual disability, 030105 genetics & heredity, Bioinformatics, Epilepsy, Neurodevelopmental disorder, CORE, Protein Phosphatase 2, SPECIFICITY, Genetics (clinical), PROTEIN PHOSPHATASE 2A, Phenotype, Hypotonia, FAMILY, 3. Good health, PP2A, [SDV] Life Sciences [q-bio], PPP2R1A, PPP2R5D, INSIGHTS, intellectual disability, Muscle Hypotonia, medicine.symptom, Language delay, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, business.industry, Macrocephaly, DEPHOSPHORYLATION, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, SUBUNIT, epilepsy, Human medicine, TAU, business, Transcription Factors
Abstract: PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported. ispartof: Genetics In Medicine vol:23 issue:2 ispartof: location:United States status: Published online
Published: 2020

34. De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author: Bertrand Isidor, Rami Abou Jamra, Virginie Carmignac, Yannis Duffourd, Helio Pedro, Eriko Koshimizu, Maja Hempel, Tobias Bartolomaeus, Martin Chevarin, Floor A. M. Duijkers, Maria J. Guillen Sacoto, Erin Torti, David Geneviève, David J. Harris, Valerie Loik Ramey, Klaske D. Lichtenbelt, Arthur Sorlin, Miriam Maik, Anne Guimier, Paul Kuentz, Tatjana Bierhals, Orly Elpeleg, Yoshiko Murakami, Laurence Faivre, Jean Baptiste Rivière, Jill Clayton-Smith, Laurent Pasquier, Yuichi Abe, Edgard Verdura, Aviva Fattal, Judith St-Onge, Daphné Lehalle, Joerg Betschinger, Krista Sondergaard-Schatz, Laurie Simone, Christa W. Habela, Ivon Cusco, Mieke M. van Haelst, Pierre Vabres, Laurence Duplomb, Magali Avila, Sakoto Miyakate, Koen L.I. van Gassen, Julien Thevenon, Eveline S. J. M. de Bont, Benjamin Cogné, Pia Zacher, Silvana van Koningsbruggen, Thibaud Jouan, Irene Valenzuela, Christel Thauvin-Robinet, Salvy-Córdoba, Nathalie, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), GeneDx [Gaithersburg, MD, USA], National Center for Child Health and Development [Tokyo], University Hospital Leipzig, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Vall d'Hebron University Hospital [Barcelona], University Medical Center Groningen [Groningen] (UMCG), VU University Medical Center [Amsterdam], Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Tel Aviv Sourasky Medical Center [Te Aviv], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Boston Children's Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Brain Centre Rudolf Magnus [Utrecht], University Medical Center [Utrecht], Hackensack University Medical Center [Hackensack], Yokohama City University (YCU), Osaka University [Osaka], CHU Pontchaillou [Rennes], Johns Hopkins University School of Medicine [Baltimore], Child Health and Human Development Program [Montréal, QC, Canada], McGill University Health Center [Montreal] (MUHC), Centre Hospitalier Universitaire [Grenoble] (CHU), University Hospital Erlangen = Uniklinikum Erlangen, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Kleinwachau - Saxon Epilepsy Center Radeberg, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, MESH: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Intellectual disability, TFE3, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Intellectual Disability, 03 medical and health sciences, Exon, 0302 clinical medicine, MESH: Whole Exome Sequencing, MESH: Child, Genetics, medicine, Missense mutation, Gene, Genetics (clinical), Exome sequencing, Pigmentary mosaicism, MESH: Pathology, Molecular, MESH: Adolescent, MESH: Humans, Alternative splicing, Lysosomal metabolism, MESH: Child, Preschool, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Adult, medicine.disease, Phenotype, MESH: Infant, MESH: Male, Storage disorder, 030104 developmental biology, MESH: Genes, X-Linked, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Young Adult, MESH: Epilepsy, MESH: Mosaicism, MESH: Pigmentation Disorders, MESH: Female, 030217 neurology & neurosurgery
Abstract: IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.
Published: 2020

35. Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Author: Florence Petit, Clémence Vanlerberghe, Thomas Smol, Fabienne Giuliano, M.F. Odou, Sylvie Manouvrier-Hanu, Perrine Brunelle, William Dufour, Malika Balduyck, Fabienne Escande, Jamal Ghoumid, Marion Gérard, Philippe Khau Van Kien, Gilles Morin, Cindy Colson, Alice Goldenberg, Elise Brischoux-Boucher, Anne Dieux, Daphné Lehalle, Anne-Sophie Jourdain, Sébastien Moutton, Simon Boussion, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de dynamique des systèmes neuroendocriniens, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Laboratoire Pierre Süe (LPS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pôle de Biologie Pathologie Génétique [CHU Lille], Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Inserm, Université de Lille, Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Maladies RAres du DÉveloppement embryonnaire et du Métabolisme : du phénotype au génotype et à la Fonction (RADEME) - ULR 7364, CIC CHU ( Lille)/inserm, Centre Hospitalier Régional Universitaire de Besançon [CHRU Besançon], Service de Génétique Clinique [CHU Caen], Université de Lausanne = University of Lausanne [UNIL], Hôpital Universitaire Carémeau [Nîmes] [CHU Nîmes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon], Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME], and Richard, Nicolas
Subjects: Male, Candidate gene, limb malformation, molecular diagnosis, targeted high-throughput sequencing, genetics, DNA Copy Number Variations, DNA Mutational Analysis, Limb Deformities, Congenital, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Real-Time Polymerase Chain Reaction, Bioinformatics, DNA sequencing, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Multiplex, Genetic Testing, Uncertain significance, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Likely pathogenic, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, Phenotype, 3. Good health, Radiography, Clinical Practice, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female
Abstract: International audience; Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high-throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3-year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy-number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high-throughput sequencing works as an efficient and cost-effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.
Published: 2020

36. Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation

Author: Christel Thauvin-Robinet, Véronique Darmency, Jean-Baptiste Rivière, Arthur Sorlin, Pierre Vabres, Marc Bardou, Frédéric Huet, Nawale Hadouiri, Alexis Arzimanoglou, Laurent Guibaud, Maxime Luu, Laurence Faivre, Virginie Carmignac, CCSD, Accord Elsevier, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Université de Bourgogne (UB)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Dijon
Subjects: 0301 basic medicine, Oncology, Compassionate Use Trials, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Muscle hypertrophy, Craniofacial Abnormalities, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, Everolimus, Child, Mechanistic target of rapamycin, Protein Kinase Inhibitors, Genetics (clinical), PI3K/AKT/mTOR pathway, Hypopigmentation, biology, business.industry, Mosaicism, TOR Serine-Threonine Kinases, Neuropsychology, General Medicine, Cortical dysplasia, medicine.disease, 3. Good health, Clinical trial, Malformations of Cortical Development, [SDV] Life Sciences [q-bio], 030104 developmental biology, Phenotype, Gain of Function Mutation, biology.protein, Female, Epilepsies, Partial, medicine.symptom, business, medicine.drug
Abstract: The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.
Published: 2020

37. Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia

Author: J. Küsel, Julien Thevenon, Emmanuelle Bourrat, Steffen Hörer, Rudolf Happle, Lisa Heinz, Pierre Vabres, Svenja Alter, Alrun Hotz, Andreas Zimmer, Judith Fischer, Fakultät für Biologie = Faculty of Biology [Freiburg], Albert-Ludwigs-Universität Freiburg, Center for Human Genetics Freiburg, Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD (CHU de Dijon), University of Freiburg [Freiburg], Department of Dermatology, University Medical Center Freiburg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and FHU TRANSLAD
Subjects: Adult, Zygote, DNA Mutational Analysis, Dermatology, Biology, Postzygotic mutation, medicine.disease_cause, PORCN, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Missense mutation, Goltz syndrome, Skin, Genetics, Mutation, Mosaicism, Mouth Mucosa, Genetic disorder, High-Throughput Nucleotide Sequencing, Membrane Proteins, cutaneous mosaicism, Karyotype, medicine.disease, Focal dermal hypoplasia, 3. Good health, focal dermal hypoplasia, Female, Klinefelter syndrome, Acyltransferases, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Focal dermal hypoplasia (FDH, Goltz syndrome, MIM: #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In males, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are males presenting either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is thereby of practical importance to analyse DNA from the affected skin in order to identify low level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads. This article is protected by copyright. All rights reserved.
Published: 2018

38. Recherche des bases moléculaires des phénotypes extrêmes de cancer par séquençage d'exome

Author: Chevarin, Martin, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), and Chevarin, Martin
Subjects: ATR, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Prédisposition, Exome, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Phénotype extrême, Cancer
Abstract: Certains cancers peuvent être qualifiés de « phénotypes extrêmes ». Il s’agit soit de formes sporadiques particulièrement précoces, soit de formes familiales avec un excès de cancers dans une même branche parentale. La présence de plusieurs tumeurs primitives, de tumeurs bilatérales ou l'association de plusieurs cancers rares chez un même patient ou au sein d’une même famille, peut également entrer dans cette catégorie. Devant ces présentations, une prédisposition génétique est très fortement suspectée.L'analyse de panels de gènes connus pour être impliqués dans les formes mendéliennes de cancer est la pratique courante pour identifier la mutation responsable d'une prédisposition au cancer. Cependant, elle ne permet d’identifier la mutation responsable de la prédisposition génétique que dans 10% des cas. Il reste donc de nombreuses cas avec une prédisposition génétique au cancer indiscutable mais sans diagnostique moléculaire. Cela représente une difficulté majeure pour les oncogénéticiens souhaitant proposer une surveillance et un conseil génétique des plus adaptés aux patients et à leurs apparentés.Le séquençage de l’exome, de 27 patients présentant des phénotypes extrêmes de cancer, a permis d'identifier 9 gènes candidats pour une prédisposition génétique au cancer :- Trois de ces gènes candidats (ATR, DLC1 et TP53I3) ont été retrouvés à partir de cas familiaux de cancers du sein masculin, un cancer particulièrement rare. Le séquençage ciblé de ces gènes dans une cohorte de réplication a permis d’identifier des récurrences pour ATR et DLC1 et des analyses fonctionnelles ont permis de préciser la pathogénicité des certaines de ces variations.- Deux variations ont été identifiées dans des gènes déjà connus comme responsables de prédisposition génétique au cancer. L’une d’elle a été identifiée dans le gène PALB2 avec une localisation de cancer pulmonaire inhabituelle, diagnostiqué à 26 ans. La seconde est une variation hétérozygote du gène BLM dans un cancer de l’ovaire à 30 ans.- Les quatre autres variations candidates concernent des gènes impliqués dans les processus d’apoptose (BIK et DFFA), de régulation épigénétique (SETD2) ou de régulation de la prolifération cellulaire (FAT4).Ces résultats montrent la pertinence d'utiliser le séquençage d’exome et une approche de phénotypes extrêmes pour identifier des variations rares dans de nouveaux gènes candidats de prédisposition au cancer.
Published: 2019

39. Pathology of Rotavirus-driven Multiple Organ Failure in a 16-month-old Boy

Author: Patrick Callier, Georges Tarris, Alexis de Rougemont, Frédéric Huet, Laurent Martin, Gaël Belliot, Laboratoire de sérologie-virologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre National de Référence des virus entériques [CHU de Dijon] (CNR virus entériques), Service de Pathologie [CHU de Dijon], Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])
Subjects: Microbiology (medical), Male, Rotavirus, Fatal outcome, Multiple Organ Failure, Autopsy, medicine.disease_cause, Rotavirus Infections, 03 medical and health sciences, 0302 clinical medicine, Fatal Outcome, Antigen, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030225 pediatrics, medicine, Humans, 030212 general & internal medicine, Human histo-blood group antigens, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Fetal Growth Retardation, Growth retardation, business.industry, Rotavirus severe acute gastroenteritis, Infant, virus diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Nephrons, Acute gastroenteritis, Acute Kidney Injury, Shock, Septic, 3. Good health, Gastroenteritis, Rotavirus infection, Infectious Diseases, Pediatrics, Perinatology and Child Health, Immunology, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Autopsy investigation of a fatal case of rotavirus severe acute gastroenteritis and multiple organ failure in a 16-month boy with previous intrauterine growth retardation showed colocalization of nonstructural and structural rotavirus proteins within viroplasms in nephrons. This case brings new insights into extraintestinal rotavirus infection and new clues to its abilities to bind to human histo-blood group antigens.
Published: 2019

40. Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid‐sparing effect

Author: Bruno Sassolas, Frédéric Caux, Olivier Dereure, Saskia Ingen-Housz-Oro, E. Csinady, Estelle Houivet, D.M. Chen, Jean-David Bouaziz, C. Prost‐Squarcioni, S. Duvert-Lehembre, Sébastien Calbo, P. Bernard, Pierre Vabres, Nicolas Dupin, L. Gearhart, Pascal Joly, Laurent Machet, Jacques Benichou, A. Odueyungbo, Carle Paul, Philippe Musette, Gaëlle Quéreux, Sébastien Debarbieux, Alain Dupuy, Catherine Picard-Dahan, Nathalie Beneton, Emmanuel Delaporte, Maud Maho-Vaillant, Michel D'Incan, Marie-Laure Golinski, Denis Jullien, Frédérique Caillot, P.B. Lehane, Marie Aleth Richard, Bruno Labeille, Laurent Misery, Christophe Bedane, M. Alexandre, Vivien Hébert, Martine Avenel-Audran, M. Cheu, Marie Beylot-Barry, Service de Dermatologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de biostatistiques [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), University Hospital of St-Etienne, Department of Dermatology, Service de dermatologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'oncologie [Hôpital privé Toulon Hyères : Sainte Marguerite], Hôpital privé Toulon Hyères : Sainte Marguerite, Commissariat à l'Energie Atomique (CEA), Institut de Biologie et Technologies de Saclay, Hôpital Henri Mondor, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital Claude Huriez [Lille], CHU Lille, Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Institut Laue-Langevin (ILL), Calcul Thermodynamique, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Centre Hospitalier Universitaire de Reims (CHU Reims), Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC), Université de Reims Champagne-Ardenne (URCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, ILL, Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Hôpital Charles Nicolle [Rouen], Service de Dermatologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])
Subjects: medicine.medical_specialty, Prednisolone, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Dermatology, Gastroenterology, law.invention, Antibodies, Monoclonal, Murine-Derived, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Prednisone, Internal medicine, Humans, Immunologic Factors, Medicine, In patient, Adverse effect, ComputingMilieux_MISCELLANEOUS, business.industry, Standard treatment, Pemphigus vulgaris, Original Articles, medicine.disease, Clinical Trial, 3. Good health, Treatment Outcome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, business, Adjuvant, Immunosuppressive Agents, Pemphigus, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Summary Background Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid‐related adverse events (AEs) is unproven. Objectives To utilize data collected in a French investigator‐initiated, phase III, open‐label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV. Methods This was an independently conducted post hoc analysis of the moderate‐to‐severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg−1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg−1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24‐month efficacy and safety results were also reported. Results At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab‐plus‐prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS‐related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone. Conclusions In patients with moderate‐to‐severe PV, rituximab plus short‐term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life‐threatening CS‐related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus.Corticosteroids, a standard first‐line treatment for PV, have significant side‐effects.Although their effects are unproven, adjuvant corticosteroid‐sparing agents are routinely used to minimize steroid exposure and corticosteroid‐related side‐effects.There is evidence that the anti‐CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator‐initiated trial.Rituximab plus prednisone had a steroid‐sparing effect and more patients achieved complete remission off prednisone.Fewer patients experienced grade 3 or grade 4 steroid‐related adverse events than those on prednisone alone.This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate‐to‐severe PV., Linked Comment: Scorer et al. Br J Dermatol 2020; 182:1078–1079.
Published: 2019

41. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Author: Sonal Mahida, Elliott H. Sherr, Elodie Lacaze, William B. Dobyns, Kosuke Izumi, Hilde Peeters, Marielle Alders, Catherine Nowak, Dawn L. Earl, Richard M. Gronostajski, Ryan J. Dean, Megan T. Cho, Anouck Schneider, Siren Berland, Patricia Blanchet, Laurence Faivre, Martin Zenker, Ina Schanze, Caitlin J. Bridges, Daniela T. Pilz, Sangamitra Boppudi, Ilse Wieland, Jens Bunt, Avni Santani, Jessica Douglas, Elaine H. Zackai, Muriel Holder-Espinasse, Linda J. Richards, Jean Baptiste Rivière, Tania Attié-Bitach, Timothy J. Edwards, Vincent Gatinois, Jacques Puechberty, Jonathan W. C. Lim, Ghayda Mirzaa, Sian Morgan, Phillis Lakeman, Steven Boogert, Samuel Huth, Marion Gérard, Denny Schanze, Florence Petit, Xiaonan Zhao, Eyal Reinstein, David Geneviève, Bronwyn Kerr, Dian Donnai, Constance Smith-Hicks, Brieana Fregeau, Amsterdam Reproduction & Development (AR&D), ACS - Pulmonary hypertension & thrombosis, Human Genetics, Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Queensland Brain Institute, University of Queensland [Brisbane], University of Amsterdam [Amsterdam] (UvA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Haukeland University Hospital, University of Bergen (UiB), GeneDx [Gaithersburg, MD, USA], University of Washington [Seattle], Seattle Children’s Hospital, University of Manchester [Manchester], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), University of California [San Francisco] (UC San Francisco), University of California (UC), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Lille, Children’s Hospital of Philadelphia (CHOP ), Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Kennedy Krieger Institute [Baltimore], University Hospital of Wales (UHW), University Hospitals Leuven [Leuven], University of Glasgow, Sackler Faculty of Medicine, Tel Aviv University (TAU), Perelman School of Medicine, University of Pennsylvania, This work was supported by grants from the National Healthand Medical Research Council Australia (GNT1100443 to L.J.R.), the French Ministry of Health (PHRC national 2008/2008-A00515-50), Regional Council of Burgundy/Dijon University hospital (PARI 2012), The Genesis Foundation for Children, the US National Institutes of Health under NINDS grants(1R01NS092772 and 234567890 to W.B.D., 1R01NS058721 toW.B.D. and E.H.S., and K08NS092898 to G.M.M.), and Jordan’s Guardian Angels (G.M.M.). J.W.C.L. was supported by an International Postgraduate Research Scholarship and UQ Centennial Scholarship. R.M.G. was supported by NYSTEM grants (C026714,C026429, and C030133). R.J.D. was supported by Brain Injured Children’s Aftercare Recovery Endeavours (BICARE) Fellowship.L.J.R. was supported by an NHMRC Principal Research Fellowship(GNT1005751). M.Z. was supported by a grant from the GermanMinistry of Education and Research (BMBF) (GeNeRARe01GM1519A). We acknowledge the Linkage Infrastructure, Equipment and Facilities (LIEF) grant (LE100100074) awarded to the Queensland Brain Institute for the Slide Scanner and the facilities of the National Imaging Facility (NIF) at the Centre for Advanced Imaging, University of Queensland, used in the animal experiments., European Project: 270259,EC:FP7:ICT,FP7-ICT-2009-6,TBICARE(2011), Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), Seattle Children's Research Institute, Department of Neurology (University of California : San Francisco), University of California [San Francisco] (UCSF), University of California-University of California, Department of Medical Genetics, HMNC Brain Health, Seattle Children’s Hospital [Seattle, WA, USA], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Université de Lorraine (UL), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Pediatrics (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Regional Genetic Service, St Mary's Hospital, Manchester, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales, Center for Human Genetics, University Hospitals Leuven, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Institute, Meir Medical Center, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, School of Computer Science and Technology, Northwestern Polytechnical University [Xi'an] (NPU), Department of Biochemistry and Developmental Genomics Group, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY)-State University of New York (SUNY)-Center of Excellence in Bioinformatics and Life Sciences, Institute of Human Genetics, University Hospital Magdeburg, université de Bourgogne, LNC, Evidence based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries - TBICARE - - EC:FP7:ICT2011-02-01 - 2014-07-31 - 270259 - VALID, Otto-von-Guericke University [Magdeburg] (OVGU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of California, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital of Wales [Cardiff, UK], and Tel Aviv University [Tel Aviv]
Subjects: Male, 0301 basic medicine, chromosome 9p23, Medical and Health Sciences, Corpus Callosum, Cohort Studies, Mice, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Agenesis of the corpus callosum, Genetics (clinical), Pediatric, Genetics & Heredity, Cerebral Cortex, Mice, Knockout, Genetics, Single Nucleotide, nuclear factor I, Biological Sciences, NFIB, NFIX, developmental delay, Mental Health, Codon, Nonsense, NFIA, intellectual disability, Child, Preschool, chromosome 9p22.3, Neurological, Speech delay, Female, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Knockout, Intellectual and Developmental Disabilities (IDD), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, macrocephaly, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Rare Diseases, Behavioral and Social Science, medicine, megalencephaly, Animals, Humans, Polymorphism, Codon, Preschool, Neurosciences, Macrocephaly, medicine.disease, Brain Disorders, haploinsufficiency, NFI Transcription Factors, 030104 developmental biology, Nonsense, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, agenesis of the corpus callosum
Abstract: The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:5 pages:752-768 ispartof: location:United States status: published
Published: 2018

42. Correction: The landscape of epilepsy-related GATOR1 variants

Author: Johannes R. Lemke, Thomas Dorn, Laura Hernandez-Hernandez, Giuseppe d'Orsi, Eveline Hagebeuk, Annapurna Poduri, Douglas R. NordliJr, Hélène Catenoix, Melanie Jennesson, Veronique Darmency, Kevin Rostasy, Thomas Becher, Laura Licchetta, Peter Uldall, Lysa Boissé Lomax, Bianca Berghuis, Ilona Krey, Gaetan Lesca, Anne de Saint Martin, Boudewijn Gunning, Anne Fabienne Lepine, Renske Oegema, Brigitte Ricard-Mousnier, Sarah Ferrand-Sorbets, Arnaud Biraben, Charles Deckers, An Sofie Schoonjans, Martin Zenker, Simona Balestrini, Inga Talvik, Julitta de Bellescize, Christopher J. Yuskaitis, Georg Dorfmüller, Erik H. Niks, Guillaume Achaz, Laurence Faivre, Pasquale Striano, Shifteh Sattar, Karen Müller-Schlüter, Sanjay M. Sisodiya, Caroline Nava, Pia Zacher, Fabrice Bartolomei, Kristin Lindstrom, Sophie Julia, Eric LeGuern, Thomas Cloppenborg, Rikke S. Møller, Antonio Gambardella, Mathilde Chipaux, Sara Baldassari, Pavel Krsek, Marie Line Jacquemont, Ilse Wegner, Christian Brandt, Barbora Benova, Valerio Conti, Gabrielle Rudolf, Floor E. Jansen, Edouard Hirsch, S. Krithika, Jamel Chelly, Katrien Stouffs, Daniëlle de Jong, Courtney Kiss, Tilman Polster, Eva H. Brilstra, Tommaso Pippucci, Markus Wolff, Cécile Marchal, Giovanni Crichiutti, Kees P.J. Braun, Paolo Tinuper, Stéphanie Baulac, Valentin Sander, Anne-Sophie Lebre, Nienke E. Verbeek, Anna Jansen, Francesca Bisulli, Fabienne Picard, Natasha E. Schoeler, Julien Thevenon, Marjan J. A. van Kempen, Guido Rubboli, Sarah Weckhuysen, Renzo Guerrini, Eleni Panagiotakaki, Meral Balci, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Universitaire de Genève, Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Children's Hospital A. Meyer, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Molecular Cell Biology, Leiden University Medical Center (LUMC), Danish Epilepsy Centre, Denmark and Aarhus University, Aarhus, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurogénétique Moléculaire et Cellulaire, Institut Naltional de la Santé et de la Recherche Médicale, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Regional Epilepsy Center, Reggio Calabria, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Département de Sociologie [université de Bourgogne], UFR de sciences humaines [Université de Bourgogne], Université de Bourgogne (UB)-Université de Bourgogne (UB), Service de Neurophysiologie Clinique (CHU Dijon), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Universitair Ziekenhuis Brussel, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Institute of Human Genetics, University Hospital Magdeburg, Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), University of Southern Denmark (SDU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Universiteit Leiden-Universiteit Leiden, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0303 health sciences, business.industry, Published Erratum, MEDLINE, medicine.disease, computer.software_genre, Spelling, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine, Artificial intelligence, business, Psychology, computer, 030217 neurology & neurosurgery, Genetics (clinical), Natural language processing, 030304 developmental biology
Abstract: International audience; The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.
Published: 2019

43. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability

Author: Florence Demurger, Christine Binquet, Muriel Holder, Frédéric Tran Mau-Them, Salima El Chehadeh, Martine Doco-Fenzy, Geneviève Baujat, Delphine Héron, Judith St-Onge, Christophe Philippe, Elodie Gautier, Robert Olaso, Rebecca A. Barnard, Paul Kuentz, François Lecoquierre, Stanislas Lyonnet, Gwenaëlle Collod-Béroud, Dominique Martin-Coignard, Isabelle Missotte, Anne Boland, Cyril Goizet, Laurence Perrin, Valérie Cormier-Daire, Sébastien Moutton, Nadine Hanna, Jean-François Deleuze, Audrey Putoux, Guillaume Jondeau, Sylvie Odent, Doris Lechner, Arnold Munnich, Thibaud Jouan, Aurélia Jacquette, Pierre-Simon Jouk, Martin Chevarin, Virginie Carmignac, Elisabetta Lapi, Alice Goldenberg, Christel Thauvin-Robinet, Sujatha Jagadeesh, P. Callier, Fatma Daoud, Yannis Duffourd, Frédéric Huet, Nathalie Marle, Charlotte Poe, Gipsy Lopez, Cyril Mignot, Florence Petit, Khadija Amarof, Brian J. O'Roak, Caroline Cabret, Fanny Morice-Picard, Jean Baptiste Rivière, Mirna Assoum, Marie Ange Delrue, Julien Thevenon, Laurence Faivre, David Geneviève, Elisabeth Sarrazin, Ange Line Bruel, Pauline Arnaud, Catherine Boileau, Christine Coubes, Didier Lacombe, Laurence Duplomb, Alice Masurel, Patrick Collignon, Antonio Vitobello, Julien Van-Gils, Bruno Leheup, Nolwenn Jean-Marçais, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Le Mans (CH Le Mans), CHU Pitié-Salpêtrière [AP-HP], Hôpital Robert Debré Paris, Hôpital Robert Debré, Hospices Civils de Lyon (HCL), CHU de la Martinique [Fort de France], Hôpital Pierre Zobda-Quitman [CHU de la Martinique], Centre hospitalier territorial Gaston-Bourret [Nouméa], CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire de Reims (CHU Reims), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Proband, Male, [SDV]Life Sciences [q-bio], intellectual deficiency, MESH: NFI Transcription Factors, chromatin remodeling, Marfan Syndrome, Craniofacial Abnormalities, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Mental Retardation, X-Linked, Exome, Child, de novo variants, Genetics (clinical), Exome sequencing, Genetics, MESH: Exome, MESH: Middle Aged, biology, MESH: Genetic Predisposition to Disease, Middle Aged, NFIX, MESH: Young Adult, Female, Adult, MESH: Mutation, Adolescent, Chromatin remodeling, MESH: Intellectual Disability, MESH: Marfan Syndrome, EHMT1, Young Adult, MESH: Whole Exome Sequencing, Intellectual Disability, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, marfanoid habitus, Gene, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, Genetic heterogeneity, MESH: Chromatin Assembly and Disassembly, MESH: Histone-Lysine N-Methyltransferase, MESH: Adult, Histone-Lysine N-Methyltransferase, medicine.disease, Chromatin Assembly and Disassembly, MESH: Male, NFI Transcription Factors, Neurodevelopmental Disorders, Mutation, biology.protein, Mental Retardation, X-Linked, MESH: Female
Abstract: PurposeMarfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.MethodsTo further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.ResultsWe identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.ConclusionWe demonstrated that DNVs were enriched in chromatin remodelling (p=2×10−4) and genes regulated by the fragile X mental retardation protein (p=3×10−8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
Published: 2019

44. The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Author: Jenny C. Taylor, Delphine Héron, Yline Capri, Lara Hawkes, Michel Koenig, Cyril Mignot, Myrthe van den Born, Usha Kini, Gabriela E. Jones, John Taylor, Renato Borgatti, Juliette Piard, Laurent Villard, Marie-Ange Nguyen-Morel, Romina Romaniello, Debbie Shears, Yoshimi Sogawa, Mélanie Fradin, Pradeep Vasudevan, Caroline Nava, Agathe Roubertie, Helen V. Firth, Christophe Philippe, Elise Brischoux-Boucher, Diana Johnson, Tiffany Busa, Mathieu Milh, Oana Tarta Arsene, Alistair T. Pagnamenta, Marie-Christine Nougues, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Oxford University Hospitals NHS Trust, University of Oxford, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), IRCCS Eugenio Medea, IRCCS, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Robert Debré Paris, Hôpital Robert Debré, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Oxford NIHR Biomedical Research Centre, Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Department of Clinical Genetics, Sheffield Children's NHS Foundation Trust, University Hospitals Leicester, CHU de Grenoble-Alpes, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Health Innovation Challenge Fund, University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent, Clinical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, WWOX, Male, Adolescent, DNA Copy Number Variations, Encephalopathy, Mutation, Missense, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Compound heterozygosity, Article, 03 medical and health sciences, symbols.namesake, Genotype, medicine, Humans, Multiplex ligation-dependent probe amplification, Child, Genetics (clinical), Exome sequencing, Genetic Association Studies, Sanger sequencing, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Tumor Suppressor Proteins, Infant, Correction, Syndrome, medicine.disease, encephalopathy, 3. Good health, 030104 developmental biology, WW Domain-Containing Oxidoreductase, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Mutation, Spinocerebellar ataxia, symbols, epilepsy, Female, business, Epileptic Syndromes
Abstract: IF 9.937 (2017); International audience; PurposeGermline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.MethodsWe report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing).ResultsTwo copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.ConclusionGermline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome. We report here 20 additional patients with biallelic pathogenic variants in the WWOX gene associated with severe early-onset encephalopathy. After a literature review, we define the main linical features of the WWOX-related disorders and discuss genotype–phenotype correlations.
Published: 2019

45. Malignant transformation of presacral mass in Currarino syndrome

Author: P. Ravasse, Ossama Yacoub, Célia Crétolle, Julien Rod, Caroline Jacquot, Sabine Sarnacki, Nicolas Cheynel, Laurence Faivre, Service de Chirurgie Pédiatrique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, CHU Dijon, Bodescot, Myriam, and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, business.industry, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Malignant transformation, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Presacral mass, Medicine, 030211 gastroenterology & hepatology, Radiology, business, Currarino syndrome, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

46. Am J Hum Genet

Author: Robert Smigiel, Géraldine Joly-Helas, Linyan Meng, Gregory M. Cooper, Nolwenn Jean-Marçais, Christel Thauvin-Robinet, Bruno Kieffer, Christopher T. Gordon, Laurence Faivre, Rhonda E. Schnur, Sarah L. Dugan, Seema R. Lalani, Heather C Mefford, Susan M. Hiatt, Marlène Rio, Seiamak Bahram, Jamel Chelly, Caroline Schluth-Bolard, Tatiana Tvrdik, Alison M. Muir, Eva Erdmann, Aline Kolmer, Aurore Garde, Angélique Pichot, Raphael Carapito, Mary K. Kukolich, Andrea M. Lewis, David Hunt, Clémantine Dimartino, Aurore Morlon, Anne Molitor, Ingrid M. Wentzensen, Fabien Dutreux, Nicodème Paul, Carlos A. Bacino, Nina B. Gold, Frédéric Tran Mau-Them, Olaf Bodamer, Deciphering Developmental Disorders Study, Zijie Sun, Pinar Bayrak-Toydemir, Heather P. Crawford, Victoria Harrison, Jocelyn Céraline, Jeanne Amiel, Mira Kharbanda, Christina Hung, A. Hanauer, Anne-Marie Guerrot, David Viskochil, Bertrand Isidor, Maya Chopra, Kirsty McWalter, Lydie Naegely, Meredith Phillips, Xia Wang, Rafał Płoski, Noel Mensah-Bonsu, Ekaterina L. Ivanova, Magalie S. Leduc, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Developmental Disabilities, Aucun, Biology, 030226 pharmacology & pharmacy, Transactivation, 03 medical and health sciences, Mice, Neurodevelopmental disorder, 0302 clinical medicine, Report, Intellectual Disability, Coactivator, medicine, Genetics, Animals, Humans, Point Mutation, Allele, Child, Exome, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, Point mutation, Correction, Infant, Syndrome, medicine.disease, Androgen receptor, 030104 developmental biology, Child, Preschool, Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.
Published: 2019

47. Prospective interest in deploying multi-omics approaches to solve unsolved patients with suspected monogenic developmental delay syndromes

Author: Duffourd, Y., Tisserant, E., Plagos, A., Callier, P., Tran-Them, F. Mau, Bruel, A., Denomme-Pichon, A., Philippe, C., Isidor, B., Heide, S., Afenjar, A., Rodriguez, D., Mignot, C., Heron, D., Vincent, M., Charles, P., Moutton, S., Jean, N., Odent, S., Dubourg, C., Faudet, A., Keren, B., Cogne, B., Boland, A., Olaso, R., Thauvin, C., Faivre, L., Deleuze, Jean-Francois, Vitobello, A., Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Plateau technique de Biologie [CHU de Dijon], Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Dijon, Jonchère, Laurent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

48. Supraventricular tachycardias, conduction disease, and cardiomyopathy in 3 families with the same rare variant in TNNI3K (p.Glu768Lys)

Author: Lindsey Miller, Merujan Y. Uzunyan, Elisabeth M. Lodder, David J. Tester, Julian Delanne, Hai Yun Yen, Géraldine Bertaux, Michael J. Ackerman, Connie R. Bezzina, Apichai Khongphatthanayothin, Shoji Yano, Sylvie Falcon-Eicher, Bryan C. Cannon, Hanlin Gao, Mischa Klerk, Shengnan Wu, Gabriel Laurent, Laurence Faivre, Arthur A.M. Wilde, Svitlana Podliesna, Department of Clinical and Experimental Cardiology (Heart Center, Academic Medical Center, Amsterdam), Academic Medical Center [Amsterdam, Netherlands], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Keck School of Medicine [Los Angeles], University of Southern California (USC), Mayo Clinic, Service de Cardiologie [CHU de Dijon], Fulgent Genetics (Temple City, California), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Cardiology, Graduate School, and ACS - Heart failure & arrhythmias
Subjects: Cardiomyopathy, Dilated, Male, Kinase, Adolescent, Conduction disease, Blotting, Western, DNA Mutational Analysis, Cardiomyopathy, Dilated cardiomyopathy, Magnetic Resonance Imaging, Cine, 030204 cardiovascular system & hematology, Protein Serine-Threonine Kinases, Sudden death, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Heart Conduction System, Physiology (medical), Cardiac conduction, medicine, Tachycardia, Supraventricular, Genetics, Humans, 030212 general & internal medicine, Genetic Testing, Kinase activity, Cells, Cultured, business.industry, Rare variant, TNNI3K, DNA, medicine.disease, Pedigree, Protein autophosphorylation, Supraventricular tachycardia, Junctional tachycardia, Mutation, Female, Cardiology and Cardiovascular Medicine, business
Abstract: IF 4.743 (2017); International audience; BackgroundRare genetic variants in TNNI3K encoding troponin-I interacting kinase have been linked to a distinct syndrome consisting primarily of supraventricular tachycardias and variably expressed conduction disturbance and dilated cardiomyopathy in 2 families.ObjectiveThe purpose of this study was to identify new genetic variants associated with inherited supraventricular tachycardias, cardiac conduction disease, and cardiomyopathy.MethodsWe conducted next generation sequencing in 3 independent multigenerational families with atrial/junctional tachycardia with or without conduction disturbance, dilated cardiomyopathy, and sudden death. We also assessed the effect of identified variant on protein autophosphorylation.ResultsIn this study, we uncovered the same ultra-rare genetic variant in TNNI3K (c.2302G>A, p.Glu768Lys), which co-segregated with disease features in all affected individuals (n = 23) from all 3 families. TNNI3K harboring the TNNI3K-p.Glu768Lys variant displayed enhanced kinase activity, in line with expectations from previous mouse studies that demonstrated increased conduction indices and procardiomyopathic effects with increased levels of Tnni3k.ConclusionThis study corroborates further the causal link between rare genetic variation in TNNI3K and this distinct complex phenotype, and points to enhanced kinase activity of TNNI3K as the underlying pathobiological mechanism.
Published: 2019

49. Whole Genome Sequencing of 9 patients allowed a better understanding of complex chromosomal rearrangements

Author: Girard, F., Jaillard, S., Keren, B., Lespinasse, J., Marle, N., Masurel, A., Mathieu, M., Metay, C., Portnoi, M., Prieur, F., Rio, M., Siffroi, J., Schluth-Bolard, C., Sanlaville, D., Chatron, N., Diguet, F., Rollat-Farnier, P., Uguen, K., Zillhardt, J. Lauer, Sorlin, A., Andrieux, J., Chantot-Bastaraud, S., Callier, P., Cordier, M., Dubourg, C., CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Amiens-Picardie, Hôpital Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

50. Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum

Author: Parker, Victoria, Keppler-Noreuil, Kim, Faivre, Laurence, Luu, Maxime, Oden, Neal, De Silva, Leena, Sapp, Julie, Andrews, Katrina, Bardou, Marc, Chen, Kong, Darling, Thomas, Gautier, Elodie, Goldspiel, Barry, Hadj-Rabia, Smail, Harris, Julie, Kounidas, Georgios, Kumar, Parag, Lindhurst, Marjorie, Loffroy, Romaric, Martin, Ludovic, Phan, Alice, Rother, Kristina, Widemann, Brigitte, Wolters, Pamela, Coubes, Christine, Pinson, Lucile, Willems, Marjolaine, Vincent-Delorme, Catherine, PROMISE working group,, Vabres, Pierre, Semple, Robert, Biesecker, Leslie, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge [UK] (CAM), National Human Genome Research Institute (NHGRI), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), The EMMES Corporation, National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], Uniformed Services University of the Health Sciences (USUHS), Pharmacy Department (NIH Clinical Center National, Institutes of Health), National Institutes of Health [Bethesda] (NIH), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Département de dermatologie, CHU Angers, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Queen's Medical Researche Institute, University of Edinburgh, CHU Necker - Enfants Malades [AP-HP]-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier]
Subjects: Adult, Male, Adolescent, Class I Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, PIK3CA, Middle Aged, Article, Phosphatidylinositol 3-Kinases, Phenotype, sirolimus, mosaicism, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Mutation, Humans, Abnormalities, Multiple, Female, Child, overgrowth, Growth Disorders, Aged
Abstract: PurposePIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth.MethodsThirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy.ResultsThirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.ConclusionThis study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS.
Published: 2019

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