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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
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2. 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
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3. 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
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4. 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
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5. 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
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6. 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
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7. 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
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8. 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
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9. Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome

Author: Natacha Lehman, Didier Lacombe, Delphine Héron, Frédérique Debomy, Sylvie Manouvrier, Frédéric Huet, Patrick Edery, Laurence Faivre, Sylvie Odent, Myriam Mikaty, Jennifer Gallard, Sophie Chancenotte, Sandrine Vinault, Maïté Tauber, David Geneviève, Coralie Rastel, Nicole Philip, Christine Binquet, Mathieu Bordes, Alain Verloes, Jamal Ghoumid, Elodie Gautier, Christel Thauvin-Robinet, Emilie Schmitt, Jenny Cornaton, Marie Bournez, Nolwenn Jean, Catherine Lejeune, Delphine Minot, Alice Masurel, Pierre-Henri Roux-Levy, 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), 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), 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), CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence du Syndrome de Prader-Willi, CHU Toulouse [Toulouse], 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), CHU Dijon, Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and CCSD, Accord Elsevier
Subjects: Male, 0301 basic medicine, medicine.medical_treatment, Intellectual disability, MESH: Cognition, CBCL, 030105 genetics & heredity, Cognition, Multidisciplinary approach, MESH: Child, Medicine, Child, Genetics (clinical), Rehabilitation, MESH: Hormone Replacement Therapy, Neurological Rehabilitation, Neuropsychology, Wechsler Adult Intelligence Scale, General Medicine, 3. Good health, MESH: Young Adult, Child, Preschool, Education, Special, Female, France, Prader-Willi Syndrome, Occupational therapy, medicine.medical_specialty, Adolescent, Hormone Replacement Therapy, MESH: Social Support, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Young Adult, 03 medical and health sciences, Social support, MESH: Neurological Rehabilitation, Genetics, Humans, Psychiatry, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, Social Support, medicine.disease, MESH: Male, MESH: France, Patient care management, 030104 developmental biology, MESH: Education, Special, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prader-Willi Syndrome, business, MESH: Female
Abstract: International audience; Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.
Published: 2020
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10. Genetic analysis of global faba bean diversity, agronomic traits and selection signatures

Author: Cathrine Kiel Skovbjerg, Deepti Angra, Tom Robertson-Shersby-Harvie, Jonathan Kreplak, Gabriel Keeble-Gagnère, Sukhjiwan Kaur, Wolfgang Ecke, Alex Windhorst, Linda Kærgaard Nielsen, Andrea Schiemann, Jens Knudsen, Natalia Gutierrez, Vasiliki Tagkouli, Lavinia Ioana Fechete, Luc Janss, Jens Stougaard, Ahmed Warsame, Sheila Alves, Hamid Khazaei, Wolfgang Link, Ana Maria Torres, Donal Martin O’Sullivan, Stig Uggerhøj Andersen, Aarhus University [Aarhus], University of Reading (UOR), Agroécologie [Dijon], Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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 for AgriBioscience, Bundoora, Georg-August-University = Georg-August-Universität Göttingen, Sejet Planteforædling, Nordic Seed, IFAPA Centro Alameda del Obispo, Instituto Andaluz de Investigación y Formación Agraria y Pesquera (IFAPA), Crops Research, Teagasc, Oak Park, Carlow, Natural Resources Institute Finland (LUKE), Open access funding provided by Royal Danish Library. Thework was funded by the European Union’s Horizon 2020 Programmefor Research & Innovation (grant agreement no. 727312 for theEUCLEG project, the ERA-NET Cofund SusCrop (grant no. 771134),part of the Joint Programming Initiative on Agriculture, Food Security,and Climate Change (FACCE-JPI) for the ProFaba project), InnovationFund Denmark (NORFAB: Protein for the Northern Hemisphere, grantno. 5158-00004B), and UK Research and Innovation for BEANS4N.AFRICA (grant award BB/P023509/1). The VICCI population wasdeveloped under a doctoral project between the University of Readingand Teagasc and was supported by the Irish Department of Agriculture,Food and the Marine (DAFM), under project 14/S/819 (the VirtualIrish Centre for Crop Improvement). The RSBP population was developed with the support of a PhD fellowship to Ahmed Warsame fromthe Islamic Development Bank, European Project: 771134, and European Project: 727312
Subjects: [SDV]Life Sciences [q-bio], Genetics, General Medicine, Agronomy and Crop Science, Biotechnology
Abstract: Key message We identified marker-trait associations for key faba bean agronomic traits and genomic signatures of selection within a global germplasm collection. Abstract Faba bean (Vicia faba L.) is a high-protein grain legume crop with great potential for sustainable protein production. However, little is known about the genetics underlying trait diversity. In this study, we used 21,345 high-quality SNP markers to genetically characterize 2678 faba bean genotypes. We performed genome-wide association studies of key agronomic traits using a seven-parent-MAGIC population and detected 238 significant marker-trait associations linked to 12 traits of agronomic importance. Sixty-five of these were stable across multiple environments. Using a non-redundant diversity panel of 685 accessions from 52 countries, we identified three subpopulations differentiated by geographical origin and 33 genomic regions subjected to strong diversifying selection between subpopulations. We found that SNP markers associated with the differentiation of northern and southern accessions explained a significant proportion of agronomic trait variance in the seven-parent-MAGIC population, suggesting that some of these traits were targets of selection during breeding. Our findings point to genomic regions associated with important agronomic traits and selection, facilitating faba bean genomics-based breeding.
Published: 2023
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11. Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool

Author: Tran Mau-Them, Frédéric, Delanne, Julian, Denommé-Pichon, Anne-Sophie, Safraou, Hana, Bruel, Ange-Line, Vitobello, Antonio, Garde, Aurore, Nambot, Sophie, Bourgon, Nicolas, Racine, Caroline, Sorlin, Arthur, Moutton, Sébastien, Marle, Nathalie, Rousseau, Thierry, Sagot, Paul, Simon, Emmanuel, Vincent-Delorme, Catherine, Boute, Odile, Colson, Cindy, Petit, Florence, Legendre, Marine, Naudion, Sophie, Rooryck, Caroline, Prouteau, Clément, Colin, Estelle, Guichet, Agnès, Ziegler, Alban, Bonneau, Dominique, Morel, Godelieve, Fradin, Mélanie, Lavillaureix, Alinoé, Quelin, Chloé, Pasquier, Laurent, Odent, Sylvie, Vera, Gabriella, Goldenberg, Alice, Guerrot, Anne-Marie, Brehin, Anne-Claire, Putoux, Audrey, Attia, Jocelyne, Abel, Carine, Blanchet, Patricia, Wells, Constance F., Deiller, Caroline, Nizon, Mathilde, Mercier, Sandra, Vincent, Marie, Isidor, Bertrand, Amiel, Jeanne, Dard, Rodolphe, Godin, Manon, Gruchy, Nicolas, Jeanne, Médéric, Schaeffer, Elise, Maillard, Pierre-Yves, Payet, Frédérique, Jacquemont, Marie-Line, Francannet, Christine, Sigaudy, Sabine, Bergot, Marine, Tisserant, Emilie, Ascencio, Marie-Laure, Binquet, Christine, Duffourd, Yannis, Philippe, Christophe, Faivre, Laurence, Thauvin-Robinet, Christel, 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), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Service de Gynécologie Obstétrique, Médecine Foetale et Stérilité Conjugale - Chirurgie Gynécologie et Oncologique [CHU de Dijon], Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Nord, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service de génétique médicale, 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), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Service de Gynécologie et Obstétrique [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Génétique et Centre de Diagnostic Anténatal, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Equipe Maladies Génétiques de L'Enfant et de L'Adulte, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée [Montpellier], Centre de Référence Anomalies du Développement et Syndromes Malformatifs [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Centre de Référence Anomalies du Développement et Syndromes Malformatifs [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Thorax [Nantes], Embryology and genetics of human malformation, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), Service de Génétique Médicale et Clinique, Hôpital Necker-Enfants Malades, Unité Fonctionnelle de Génétique Médicale, Cytogénétique, Génétique Médicale et Biologie de La Reproduction, Centre Hospitalier Intercommunal Poissy-Saint-Germain-en-Laye, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, UMR 1253 IBrain Imagerie & Cerveau Equipe 2 : 'Neurogénomique & Physiopathologie neuronale' (NPN), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Génétique Médicale, Pôle Femme, Mère, Enfants CHU de La Réunion-GH Sud Réunion-Saint-Pierre, Pôle Femme, Mère, Enfants, CHU de La Réunion-GH Sud Réunion-Saint-Pierre-CHU de La Réunion-GH Sud Réunion-Saint-Pierre, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de Génétique Clinique Prénatale, Département de Génétique Médicale, Hôpital de la Timone [CHU - APHM] (TIMONE)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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), and This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), the European Union through the FEDER programs, and the AnDDI-Rares network for ES performed in this study.
Subjects: prenatal, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, chromosomal microarray, exome sequencing (ES), diagnostic yield, Genetics, Molecular Medicine, fetal, Genetics (clinical)
Abstract: Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%–10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US.Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel.Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV.Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.
Published: 2023
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12. Should we screen for colorectal cancer in people aged 75 and over? A systematic review - collaborative work of the French geriatric oncology society (SOFOG) and the French federation of digestive oncology (FFCD)

Author: Lydia, Guittet, Valérie, Quipourt, Thomas, Aparicio, Elisabeth, Carola, Jean-François, Seitz, Elena, Paillaud, Astrid, Lievre, Rabia, Boulahssass, Carole, Vitellius, Leila, Bengrine, Florence, Canoui-Poitrine, Sylvain, Manfredi, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Marseille, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cancer Research and Personalized Medicine - CARPEM [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], IHFIH UPRES EA 3859, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, CHU Henri Mondor [Créteil], 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), and None
Subjects: Aged, 80 and over, Cancer Research, Harms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Colonoscopy, Comorbidity, Cost effectiveness, Life Expectancy, Acceptability, Oncology, Genetics, Humans, Mass Screening, Colorectal Neoplasms, Early Detection of Cancer, Simulation, Aged
Abstract: Background We have done a systematic literature review about CRC Screening over 75 years old in order to update knowledge and make recommendations. Methods PUBMED database was searched in October 2021 for articles published on CRC screening in the elderly, and generated 249 articles. Further searches were made to find articles on the acceptability, efficacy, and harms of screening in this population, together with the state of international guidelines. Results Most benefit-risk data on CRC screening in the over 75 s derived from simulation studies. Most guidelines recommend stopping cancer screening at the age of 75. In private health systems, extension of screening up to 80–85 years is, based on the life expectancy and the history of screening. Screening remains effective in populations without comorbidity given their better life-expectancy. Serious adverse events of colonoscopy increase with age and can outweigh the benefit of screening. The great majority of reviews concluded that screening between 75 and 85 years must be decided case by case. Conclusion The current literature does not allow Evidence-Based Medicine propositions for mass screening above 75 years old. As some subjects over 75 years may benefit from CRC screening, we discussed ways to introduce CRC screening in France in the 75–80 age group. IRB An institutional review board composed of members of the 2 learned societies (SOFOG and FFCD) defined the issues of interest, followed the evolution of the work and reviewed and validated the report.
Published: 2023
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13. Limited Transmission of Klebsiella pneumoniae among Humans, Animals, and the Environment in a Caribbean Island, Guadeloupe (French West Indies)

Author: Alexis Dereeper, Gaëlle Gruel, Matthieu Pot, David Couvin, Elodie Barbier, Sylvaine Bastian, Jean-Christophe Bambou, Moana Gelu-Simeon, Séverine Ferdinand, Stéphanie Guyomard-Rabenirina, Virginie Passet, Frederic Martino, Pascal Piveteau, Yann Reynaud, Carla Rodrigues, Pierre-Marie Roger, Xavier Roy, Antoine Talarmin, Benoit Tressieres, Marc Valette, Sylvain Brisse, Sébastien Breurec, Unité Transmission, Réservoir et Diversité des Pathogènes [Pasteur Guadeloupe, France] (TReD-Path), Institut Pasteur de la Guadeloupe, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Agroécologie [Dijon], Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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 Pointe-à-Pitre/Abymes [Guadeloupe], Agroécologie, génétique et systèmes d’élevage tropicaux (ASSET), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Optimisation des procédés en Agriculture, Agroalimentaire et Environnement (UR OPAALE), Université des Antilles - UFR des sciences médicales Hyacinthe Bastaraud (UA UFR SM), Université des Antilles (UA), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], This work was supported by a FEDER grant financed by the European Union and Guadeloupe Region (Programme Opérationnel FEDER-Guadeloupe-Conseil Régional 2014–2020, grant no. 2015-FED-192). Carla Rodrigues was supported financially by the MedVetKlebs project, a component of the One Health European Joint Programme (EJP), which has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 773830, and by a Pasteur-Roux fellowship from the Institut Pasteur., We thank the Plateforme de Microbiologie Mutualisée (P2M) of the Institut Pasteur for Illumina sequencing. We thank all of the students, technicians, and clinicians involved in this work at the Pasteur Institute of Guadeloupe and the University Hospital Center of Guadeloupe., European Project: 2015-FED-192,FEDER-Guadeloupe, and European Project: 773830,H2020-SFS-2017-1,MedVetKlebs (a component of European Joint Programme One Health)(2018)
Subjects: Caribbean, Microbiology (medical), Bacterial Zoonoses, General Immunology and Microbiology, Ecology, Physiology, Swine, Cell Biology, Microbial Sensitivity Tests, beta-Lactamases, Anti-Bacterial Agents, Klebsiella Infections, genomic, Klebsiella pneumoniae, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, Dogs, ESBL, Drug Resistance, Multiple, Bacterial, Genetics, Animals, Humans, One Health, Guadeloupe
Abstract: International audience; Guadeloupe (French West Indies), a Caribbean island, is an ideal place to study the reservoirs of the Klebsiella pneumoniae species complex (KpSC) and identify the routes of transmission between human and nonhuman sources due to its insularity, small population size, and small area. Here, we report an analysis of 590 biological samples, 546 KpSC isolates, and 331 genome sequences collected between January 2018 and May 2019. The KpSC appears to be common whatever the source. Extended-spectrum-β-lactamase (ESBL)-producing isolates (21.4%) belonged to K. pneumoniae sensu stricto (phylogroup Kp1), and all but one were recovered from the hospital setting. The distribution of species and phylogroups across the different niches was clearly nonrandom, with a distinct separation of Kp1 and Klebsiella variicola (Kp3). The most frequent sequence types (STs) (≥5 isolates) were previously recognized as high-risk multidrug-resistant (MDR) clones, namely, ST17, ST307, ST11, ST147, ST152, and ST45. Only 8 out of the 63 STs (12.7%) associated with human isolates were also found in nonhuman sources. A total of 22 KpSC isolates were defined as hypervirulent: 15 associated with human infections (9.8% of all human isolates), 4 (8.9%) associated with dogs, and 3 (15%) associated with pigs. Most of the human isolates (33.3%) belonged to the globally successful sublineage CG23-I. ST86 was the only clone shared by a human and a nonhuman (dog) source. Our work shows the limited transmission of KpSC isolates between human and nonhuman sources and points to the hospital setting as a cornerstone of the spread of MDR clones and antibiotic resistance genes.IMPORTANCE In this study, we characterized the presence and genomic features of isolates of the Klebsiella pneumoniae species complex (KpSC) from human and nonhuman sources in Guadeloupe (French West Indies) in order to identify the reservoirs and routes of transmission. This is the first study in an island environment, an ideal setting that limits the contribution of external imports. Our data showed the limited transmission of KpSC isolates between the different compartments. In contrast, we identified the hospital setting as the epicenter of antibiotic resistance due to the nosocomial spread of successful multidrug-resistant (MDR) K. pneumoniae clones and antibiotic resistance genes. Ecological barriers and/or limited exposure may restrict spread from the hospital setting to other reservoirs and vice versa. These results highlight the need for control strategies focused on health care centers, using genomic surveillance to limit the spread, particularly of high-risk clones, of this important group of MDR pathogens.
Published: 2022
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14. Efficacy of donepezil for the treatment of oxaliplatin-induced peripheral neuropathy: DONEPEZOX, a protocol of a proof of concept, randomised, triple-blinded and multicentre trial

Author: Nicolas Kerckhove, David Tougeron, Côme Lepage, Denis Pezet, Karine Le Malicot, Manon Pelkowski, Bruno Pereira, David Balayssac, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Service de Pharmacologie Médicale [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hépato-gastroentérologie et cancérologie digestive (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)-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), Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Fédération Francophone de Cancérologie Digestive (FFCD), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand, French Ministry of Health, National Institute of Cancer ('Institut National du Cancer (INCa) : Programme Hospitalier de Recherche Clinique Cancer', {20-082 PHRC-K], and Molé, Christine
Subjects: Chemotherapy-induced peripheral neuropathy, Cancer Research, Peripheral Nervous System Diseases, Pain, [SDV.CAN]Life Sciences [q-bio]/Cancer, Anticholinesterase, Oxaliplatin, Clinical Trials, Phase III as Topic, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Study protocol, Quality of Life, Genetics, Humans, Multicenter Studies as Topic, Donepezil, Randomized Controlled Trials as Topic
Abstract: Background The use of oxaliplatin in digestive tract cancers could induce severe peripheral neuropathy (OIPN) decreasing the quality of life of patients and survivors. There is currently, no univocal treatment for these peripheral neuropathies. Donepezil, a reversible inhibitor of cholinesterase, used to treat Alzheimer’s disease and dementia, is reported to have a good safety profile in humans, and preclinical data have provided initial evidence of its effectiveness in diminishing neuropathic symptoms and related comorbidities in OIPN animal models. Methods The DONEPEZOX trial will be a proof-of-concept, randomised, triple-blinded, and multicentre study. It will be the first clinical trial evaluating the efficacy and safety of donepezil for the management of OIPN. Adult cancer survivors with OIPN that report sensory neuropathy according to QLQ-CIPN20 sensory score (equivalence of a grade ≥ 2), at least 6 months after the end of an oxaliplatin-based chemotherapy will be included. Eighty patients will be randomly assigned to receive either donepezil or placebo over 16 weeks of treatment. The primary endpoint will be the rate of responders (neuropathic grade decreases according to the QLQ-CIPN20 sensory score) in the donepezil arm. The severity of OIPN will be assessed by the QLQ-CIPN20 sensory scale before and after 16 weeks of treatment. The comparison versus the placebo arm will be a secondary objective. The other secondary endpoints will be tolerance to donepezil, the severity and features of OIPN in each arm before and after treatment, related-comorbidities and quality of life. Fleming’s one-stage design will be used for sample size estimation. This design yields a type I error rate of 0.0417 and power of 91% for a responder rate of at least 30% in donepezil arm. A total of 80 randomized patients is planned. Discussion This study will allow, in the case of positive results, to initiate a phase 3 randomized and placebo-controlled (primary endpoint) clinical study to assess the therapeutic interest of donepezil to treat OIPN. Trial registration NCT05254639, clincialtrials.gov, Registered 24 February 2022.
Published: 2022
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15. The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium

Author: Thee, Eric, Colijn, Johanna, Cougnard-Grégoire, Audrey, Meester-Smoor, Magda, Verzijden, Timo, Hoyng, Carel, Fauser, Sascha, Hense, Hans-Werner, Silva, Rufino, Creuzot-Garcher, Catherine, Ueffing, Marius, Delcourt, Cécile, den Hollander, Anneke, Klaver, Caroline C.W., Epidemiology, Ophthalmology, Julien, Sabine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Bordeaux Population Health Research Center, Inserm, Bordeaux, Radboud University Medical Center [Nijmegen], University Hospital of Cologne [Cologne], F. Hoffmann-La Roche A.G., Switzerland, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Centro Hospitalar e Universitário [Coimbra], Service d'Ophtalmologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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), and University of Tübingen
Subjects: HTRA1, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Genotype, Age-related macular degeneration, Proteins, Retinal Drusen, High-Temperature Requirement A Serine Peptidase 1, Polymorphism, Single Nucleotide, Choroidal Neovascularization, Europe, Macular Degeneration, Phenotype, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Risk Factors, Complement Factor H, Humans, genetics, ARMS2, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Purpose: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium. Design: Pooled analysis of 4 case-control and 6 cohort studies. Participants: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium. Methods: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan–Meier analyses in population-based cohorts. Main Outcome Measures: Age-related macular degeneration features and stage. Results: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5–11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4–13.3), and of mixed late AMD was 12.2 (95% CI, 7.3–20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0–11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 μm (OR, 1.2; 95% CI, 0.9–1.7), but risks increased significantly for soft drusen ≥ 125 μm (OR, 2.1; 95% CI, 1.5–3.0), up to an OR of 7.2 (95% CI, 3.8–13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2–5.4); risks of other characteristics were not different. Conclusions: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.
Published: 2022
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16. <scp>Skraban‐Deardorff</scp> syndrome: Six new cases of <scp> WDR 26 </scp> ‐related disease and expansion of the clinical phenotype

Author: Laurence Faivre, Varoona Bizaoui, Christèle Dubourg, Frédéric Tran Mau-Them, Wilfrid Carré, Amélie Piton, Sylvie Odent, Lionel Van Maldergem, Ange-Line Bruel, Laurent Pasquier, Marie Faoucher, Bénédicte Gérard, Mélanie Fradin, Alinoë Lavillaureix, Auriane Cospain, Florence Demurger, Jessica Assoumani, Elise Schaefer, Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Les Hôpitaux Universitaires de Strasbourg (HUS), 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), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), Groupe Hospitalier Bretagne Sud (GHBS), 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 ), 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 Bretagne Atlantique (Morbihan) (CHBA), and Chard-Hutchinson, Xavier
Subjects: Male, 0301 basic medicine, Proband, Pediatrics, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Skraban-Deardorff syndrome, Disease, 030105 genetics & heredity, Young Adult, 03 medical and health sciences, Intellectual disability, Genetics, medicine, WDR26, Humans, Abnormalities, Multiple, hypotonia, Ataxic Gait, Child, Genetics (clinical), Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Muscle biopsy, medicine.diagnostic_test, business.industry, Infant, Syndrome, medicine.disease, Gait, Hypotonia, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, 030104 developmental biology, speech therapy, intellectual disability, Child, Preschool, Mutation, Cohort, language development disorders, Female, medicine.symptom, business
Abstract: International audience; Skraban-Deardorff syndrome (a disease related to variations in the WDR26 gene; OMIM #617616) was first described in a cohort of 15 individuals in 2017. The syndrome comprises intellectual deficiency, severe speech impairment, ataxic gait, seizures, mild hypotonia with feeding difficulties during infancy, and dysmorphic features. Here, we report on six novel heterozygous de novo pathogenic variants in WDR26 in six probands. The patients’ phenotypes were consistent with original publication. One patient displayed marked hypotonia with an abnormal muscle biopsy; this finding warrants further investigation. Gait must be closely monitored, in order to highlight any musculoskeletal or neurological abnormalities and prompt further examinations. Speech therapy and alternative communication methods should be initiated early in the clinical follow-up, in order to improve language and oral eating and drinking.
Published: 2021
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17. MtEFD and MtEFD2: Two transcription factors with distinct neofunctionalization in symbiotic nodule development

Author: Marie-Françoise Jardinaud, Justine Fromentin, Marie-Christine Auriac, Sandra Moreau, Yann Pecrix, Ludivine Taconnat, Ludovic Cottret, Grégoire Aubert, Sandrine Balzergue, Judith Burstin, Sébastien Carrere, Pascal Gamas, Laboratoire des Interactions Plantes Microbes Environnement (LIPME), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Peuplements végétaux et bioagresseurs en milieu tropical (UMR PVBMT), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université de La Réunion (UR)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité expérimentale du GEVES, Institut National de la Recherche Agronomique (INRA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Agroécologie [Dijon], Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, 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), INRAE (CJS fellowship for J.F., SPE grant 'EFFOR'), ANR-09-GENM-0026,GENOPEA,Génomique comparative du cycle de l'azote entre M. truncatula et le pois : étude des potentialités de transfert des connaissances entre espèces modèles et cultivées(2009), ANR-10-LABX-0041,TULIP,Towards a Unified theory of biotic Interactions: the roLe of environmental(2010), ANR-10-LABX-0040,SPS,Saclay Plant Sciences(2010), and Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Nitrogen, CNRS, Physiology, food and beverages, Plant Science, Ethylenes, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gene Expression Regulation, Plant, Nitrogen Fixation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicago truncatula, Genetics, Root Nodules, Plant, Symbiosis, LIPME, Research Articles, Université de Toulouse, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Plant Proteins, Transcription Factors, INRAE
Abstract: Rhizobium–legume nitrogen-fixing symbiosis involves the formation of a specific organ, the root nodule, which provides bacteria with the proper cellular environment for atmospheric nitrogen fixation. Coordinated differentiation of plant and bacterial cells is an essential step of nodule development, for which few transcriptional regulators have been characterized. Medicago truncatula ETHYLENE RESPONSE FACTOR REQUIRED FOR NODULE DIFFERENTIATION (MtEFD) encodes an APETALA2/ETHYLENE RESPONSIVE FACTOR (ERF) transcription factor, the mutation of which leads to both hypernodulation and severe defects in nodule development. MtEFD positively controls a negative regulator of cytokinin signaling, the RESPONSE REGULATOR 4 (MtRR4) gene. Here we showed that that the Mtefd-1 mutation affects both plant and bacterial endoreduplication in nodules, as well as the expression of hundreds of genes in young and mature nodules, upstream of known regulators of symbiotic differentiation. MtRR4 expressed with the MtEFD promoter complemented Mtefd-1 hypernodulation but not the nodule differentiation phenotype. Unexpectedly, a nonlegume homolog of MtEFD, AtERF003 in Arabidopsis (Arabidopsis thaliana), could efficiently complement both phenotypes of Mtefd-1, in contrast to the MtEFD paralog MtEFD2 expressed in the root and nodule meristematic zone. A domain swap experiment showed that MtEFD2 differs from MtEFD by its C-terminal fraction outside the DNA binding domain. Furthermore, clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9 (CRISPR-Cas9) mutagenesis of MtEFD2 led to a reduction in the number of nodules formed in Mtefd-1, with downregulation of a set of genes, including notably NUCLEAR FACTOR-YA1 (MtNF-YA1) and MtNF-YB16, which are essential for nodule meristem establishment. We, therefore, conclude that nitrogen-fixing symbiosis recruited two proteins originally expressed in roots, MtEFD and MtEFD2, with distinct functions and neofunctionalization processes for each of them.
Published: 2022
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18. Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice

Author: Lettie E. Rawlins, Hashem Almousa, Shazia Khan, Stephan C. Collins, Miroslav P. Milev, Joseph Leslie, Djenann Saint-Dic, Valeed Khan, Ana Maria Hincapie, Jacob O. Day, Lucy McGavin, Christine Rowley, Gaurav V. Harlalka, Valerie E. Vancollie, Wasim Ahmad, Christopher J. Lelliott, Asma Gul, Binnaz Yalcin, Andrew H. Crosby, Michael Sacher, Emma L. Baple, Rawlins, Lettie E [0000-0002-6764-253X], Almousa, Hashem [0000-0003-2679-5350], Collins, Stephan C [0000-0002-1533-3380], Leslie, Joseph [0000-0003-0972-8818], Saint-Dic, Djenann [0000-0001-9328-7108], Khan, Valeed [0000-0002-3840-5439], Day, Jacob O [0000-0002-6020-510X], Harlalka, Gaurav V [0000-0001-8968-2447], Vancollie, Valerie E [0000-0003-1547-1975], Lelliott, Christopher J [0000-0001-8087-4530], Yalcin, Binnaz [0000-0002-1924-6807], Crosby, Andrew H [0000-0003-3667-9054], Sacher, Michael [0000-0003-2926-5064], Baple, Emma L [0000-0002-6637-3411], Apollo - University of Cambridge Repository, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Concordia University [Montreal], International Islamic University [Islamabad, Pakistan] (2IU), 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), 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), Rehman Medical Institute [Peshawar, Pakistan] (RMI), Plymouth University, University Hospitals Plymouth NHS Trust [Plymouth, UK] (UHP), The Wellcome Trust Sanger Institute [Cambridge], Rajarshi Shahu College of Pharmacy [Malvihir, Buldana, India] (RSCP), Quaid-i-Azam University (QAU), McGill University = Université McGill [Montréal, Canada], and Dupuis, Christine
Subjects: [SDV] Life Sciences [q-bio], Cancer Research, Mice, Phenotype, Neurodevelopmental Disorders, [SDV]Life Sciences [q-bio], Genetics, Microcephaly, Animals, Humans, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics
Abstract: The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.
Published: 2022
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19. High Prevalence of Klebsiella pneumoniae in European Food Products: a Multicentric Study Comparing Culture and Molecular Detection Methods

Author: Dearbháile Morris, Gabriella Centorotola, Pascal Piveteau, Carla Rodrigues, Alessandra Cornacchia, Sylvain Brisse, Marisa Haenni, Niamh Cahill, Kathrin Hauser, Francesco Pomilio, Elodie Barbier, Eva Møller Nielsen, Malgorzata Ligowska-Marzeta, Raquel Garcia Fierro, Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Austrian Agency for Health and Food Safety (AGES), National University of Ireland [Galway] (NUI Galway), Statens Serum Institut [Copenhagen], Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise Guiseppe Caporale (IZSAM), Partenaires INRAE, Unité Antibiorésistance et Virulence Bactériennes (AVB), Laboratoire de Lyon [ANSES], Université de Lyon-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université de Lyon-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Agroécologie [Dijon], Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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), This work was supported financially by the MedVetKlebs project, a component of European Joint Program One Health EJP, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 773830. C.R. was also financed by a Roux-Cantarini grant from Institut Pasteur.This research was funded, in whole or in part, by Institut Pasteur and by the European Union’s Horizon 2020 research and innovation program. For the purpose of open access, the authors have applied a CC-BY public copyright license to any author manuscript version arising from this submission., We thank James Bray and Keith Jolley for technical assistance with genomic assemblies of KpSC isolates from Ireland. We thank the Institut Pasteur teams for the curation and maintenance of BIGSdb-Pasteur databases at http://bigsdb.pasteur.fr/., and European Project: 773830, H2020-SFS-2017-1 ,One Health EJP(2018)
Subjects: Microbiology (medical), Veterinary medicine, antibiotic resistance, Meat, Genotype, Physiology, Klebsiella pneumoniae, [SDV]Life Sciences [q-bio], Food Contamination, Microbial Sensitivity Tests, beta-Lactamases, Foodborne Diseases, chemistry.chemical_compound, Bacterial Proteins, Drug Resistance, Multiple, Bacterial, Genetics, culture methods, genomics, Prevalence, Animals, Humans, Colonization, One Health, Phylogeny, Genetic diversity, High prevalence, General Immunology and Microbiology, Ecology, biology, transmission, Genetic Variation, Cell Biology, Simmons' citrate agar, biology.organism_classification, food sector, Anti-Bacterial Agents, Klebsiella Infections, Europe, Food sector, Infectious Diseases, chemistry, Food products, Klebsiella pneumoniae, food sector, transmission, chicken meat, salads, antibiotic resistance, One Health, genomics, surveillance, culture methods, surveillance, Salads, chicken meat, Chickens
Abstract: Klebsiella pneumoniae species complex (KpSC) is a leading cause of multidrug-resistant human infections. To better understand the potential contribution of food as a vehicle of KpSC, we conducted a multicentric study to define an optimal culture method for its recovery from food matrices, and to characterize food isolates phenotypically and genotypically. Chicken meat (n=160) and salad (n=145) samples were collected in five European countries and screened for KpSC presence using culture-based and ZKIR qPCR methods. Enrichment using buffered peptone water followed by streaking on Simmons citrate agar with inositol (44°C/48h) was defined as the most suitable selective culture method for KpSC recovery. High prevalence of KpSC was found in chicken meat (60% and 52% by ZKIR qPCR and culture approach, respectively) and salad (30% and 21%, respectively) samples. Genomic analyses revealed high genetic diversity with the dominance of phylogroups Kp1 (91%) and Kp3 (6%). 82% of isolates presented a natural antimicrobial susceptibility phenotype and genotype, with only four CTX-M-15-producing isolates detected. Notably, identical genotypes were found across samples: same food type and same country (15 cases); different food types and same country (1); same food type and two countries (1), suggesting high rates of transmission of KpSC within the food sector. Our study provides a novel isolation strategy for KpSC from food matrices and reinforces the view of food as a potential source of KpSC colonization in humans.ImportanceBacteria of the Klebsiella pneumoniae species complex (KpSC) are ubiquitous and K. pneumoniae (Kp) is a leading cause of antibiotic-resistant infections in humans and animals. Despite the urgent public health threat represented by Kp, there is a lack of knowledge on the contribution of food sources to colonization and subsequent infection in humans. This is partly due to the absence of standardized methods for characterizing KpSC presence in food matrices. Our multicentric study provides and implements a novel isolation strategy for KpSC from food matrices and shows that KpSC members are highly prevalent in salads and chicken meat, reinforcing the view of food as a potential source of KpSC colonization in humans. Despite the large genetic diversity and the low-levels of resistance detected, the occurrence of identical genotypes across samples suggests high rates of transmission of KpSC within the food sector, which need to be further explored to define possible control strategies.
Published: 2022
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20. OncoSNIPE® Study Protocol, a study of molecular profiles associated with development of resistance in solid cancer patients

Author: Sébastien Vachenc, Jessica Gobbo, Sarah El Moujarrebe, Isabelle Desmoulins, Marine Gilabert, Michelle Beau-Faller, Emmanuel Mitry, Nicolas Girard, Aurélie Bertaut, Nelson Dusetti, Juan L. Iovanna, Rahima Yousfi, Fabien Pierrat, Roman Bruno, Adèle Cueff, Romain Boidot, Philippe Genne, Oncodesign [Dijon], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Curie [Paris], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ACOBIOM, and Malbec, Odile
Subjects: Adult, Male, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Triple negative breast or Luminal Breast Cancer, Breast Neoplasms, Triple Negative Breast Neoplasms, Pancreatic ductal adenocarcinoma, Study Protocol, Immunological profile, Carcinoma, Non-Small-Cell Lung, Neoplasms, Biomarkers, Tumor, Genetics, Humans, RC254-282, Response Evaluation Criteria in Solid Tumors, Disease Resistance, Early/ late resistance marker, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Non small-cell lung cancer, Pancreatic Neoplasms, [SDV] Life Sciences [q-bio], Oncology, Drug Resistance, Neoplasm, NGS, Female, Carcinoma, Pancreatic Ductal
Abstract: Background Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment. Methods Multicentric, interventional study with the primary objective to identify early and / or late markers of resistance to treatment, in 600 adult patients with locally advanced or metastatic triple negative or Luminal B breast cancer, non-small-cell lung cancer or pancreatic ductal adenocarcinoma. Patients targeted in this study have all rapid progression of their pathology, making it possible to obtain models for evaluating markers of early and / or late responses over the 2-year period of follow-up, and thus provide the information necessary to understand resistance mechanisms. To explore the phenomena of resistance, during therapeutic response and / or progression of the pathology, we will use a multidisciplinary approach including high-throughput sequencing (Exome-seq and RNAseq), clinical data, medical images and immunological profile by ELISA. Patients will have long-term follow-up with different biological samples, at baseline (blood and biopsy) and at each tumoral evaluation or tumoral progression evaluated by medical imaging. Clinical data will be collected through a dedicated Case Report Form (CRF) and enriched by semantic extraction based on the French ConSoRe (Continuum Soins Recherche) initiative, a dedicated Semantic Clinical Data Warehouse (SCDW) to cancer. The study is sponsored by Oncodesign (Dijon, France) and is currently ongoing. Discussion The great diversity of intrinsic or acquired molecular mechanisms involved in resistance to treatment constitutes a real therapeutic issue. Improving understanding of mechanisms of resistance of cancer cells to anti-tumor treatments is therefore a major challenge. The OncoSNIPE cohort will lead to a better understanding of the mechanisms of resistance and will allow to explore new mechanisms of actions and to discover new therapeutic targets or strategies making it possible to circumvent the escape in different types of cancer. Trial registration Clinicaltrial.gov. Registered 16 September 2020, https://clinicaltrials.gov/ct2/show/NCT04548960?term=oncosnipe&draw=2&rank=1 and ANSM ID RCB 2017-A02018-45.
Published: 2022
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21. Genome sequencing for genetics diagnosis of patients with intellectual disability: the DEFIDIAG study

Author: Christine Binquet, Catherine Lejeune, Laurence Faivre, Marion Bouctot, Marie-Laure Asensio, Alban Simon, Jean-François Deleuze, Anne Boland, Francis Guillemin, Valérie Seror, Christelle Delmas, Hélène Espérou, Yannis Duffourd, Stanislas Lyonnet, Sylvie Odent, Delphine Heron, Damien Sanlaville, Thierry Frebourg, Bénédicte Gerard, 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), 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), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), 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 ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), 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), Plan France Médecine Génomique 2025, Ministère Des Affaires Sociales et de La Santé, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-INBS-0001,France Génomique CREFIX,Utilisation des fonds du centre de référence d'innovation et d'expertise (CREFIX) du plan de médecine génomique (PFMG 2025)(2018), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL UR1, Admin, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Utilisation des fonds du centre de référence d'innovation et d'expertise (CREFIX) du plan de médecine génomique (PFMG 2025) - - France Génomique CREFIX2018 - ANR-18-INBS-0001 - INBS - VALID
Subjects: [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], minimal reference strategy, diagnostic odyssey, QH426-470, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, genome sequencing, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, Genetics, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Molecular Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], cost-effectiveness, Genetics (clinical)
Abstract: Introduction: Intellectual Disability (ID) is the most common cause of referral to pediatric genetic centers, as it affects around 1–3% of the general population and is characterized by a wide genetic heterogeneity. The Genome Sequencing (GS) approach is expected to achieve a higher diagnostic yield than exome sequencing given its wider and more homogenous coverage, and, since theoretically, it can more accurately detect variations in regions traditionally not well captured and identify structural variants, or intergenic/deep intronic putatively pathological events. The decreasing cost of sequencing, the progress in data-management and bioinformatics, prompted us to assess GS efficiency as the first line procedure to identify the molecular diagnosis in patients without obvious ID etiology. This work is being carried out in the framework of the national French initiative for genomic medicine (Plan France Médecine Génomique 2025).Methods and Analysis: This multidisciplinary, prospective diagnostic study will compare the diagnostic yield of GS trio analysis (index case, father, mother) with the French core minimal reference strategy (Fragile-X testing, chromosomal microarray analysis and Gene Panel Strategy of 44 selected ID genes). Both strategies are applied in a blinded fashion, in parallel, in the same population of 1275 ID index cases with no obvious diagnosis (50% not previously investigated). Among them, a subgroup of 196 patients are randomized to undergo GS proband analysis in addition to GS trio analysis plus the French core minimal reference strategy, in order to compare their efficiency. The study also aims to identify the most appropriate strategy according to the clinical presentation of the patients, to evaluate the impact of deployment of GS on the families’ diagnostic odyssey and the modification of their care, and to identify the advantages/difficulties for the patients and their families.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I and the French data privacy commission (CNIL, authorization 919361).Trial Registration:ClinicalTrials.gov identifier NCT04154891 (07/11/2019).
Published: 2022
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22. A positively-selected MAGEE2 LoF allele is associated with sexual dimorphism in human brain size, and shows similar phenotypes in Magee2 null mice

Author: Stephan C. Collins, Michal Szpak, Christopher J. Lelliott, Yali Xue, Chris Tyler-Smith, Yan Li, Qasim Ayub, Valerie E. Vancollie, Marie-Christine Fischer, Xiao Liu, Binnaz Yalcin, Huanming Yang, Wellcome Sanger Institute [Hinxton, Royaume-Uni], 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), Beijing Genomics Institute [Shenzhen] (BGI), Tsinghua University [Beijing] (THU), Monash University [Malaysia], 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), and univOAK, Archive ouverte
Subjects: Male, mouse knockout, Biology, Grey matter, AcademicSubjects/SCI01180, 03 medical and health sciences, Mice, 0302 clinical medicine, Retrosplenial cortex, Antigens, Neoplasm, positive selection, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Molecular Biology, Ecology, Evolution, Behavior and Systematics, X chromosome, Discoveries, Alleles, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Sex Characteristics, AcademicSubjects/SCI01130, Brain, Proteins, Organ Size, White (mutation), Sexual dimorphism, medicine.anatomical_structure, Phenotype, loss of function, brain size, sexual dimorphism, Brain size, Knockout mouse, Female, 030217 neurology & neurosurgery, MRI
Abstract: A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. This premature stop codon causing ∼80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, we generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P = 0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation, and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P = 3.4×10−6). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of gray matter in males (P = 0.00094), and smaller volumes of gray (P = 0.00021) and white (P = 0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behavior or cognition, but it might have been the driving force underlying the positive selection in humans.
Published: 2021
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23. Dissecting indirect genetic effects from peers in laboratory mice

Author: Abraham A. Palmer, Binnaz Yalcin, Oliver Stegle, Jérôme Nicod, Amanda M. Barkley-Levenson, Charlotte Montillot, Francesco Paolo Casale, Amelie Baud, Nilgoun Farhadi, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of California [San Diego] (UC San Diego), University of California (UC), Microsoft Research New England [Cambridge, MA, USA] (MRNE), 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), University of Oxford, Genome Biology Unit [Heidelberg, Germany], European Molecular Biology Laboratory [Hinxton], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), The Wellcome Trust Sanger Institute [Cambridge], and Dupuis, Christine
Subjects: 0301 basic medicine, Male, Genome-wide association study, Multifactorial Inheritance, Genotype, QH301-705.5, [SDV]Life Sciences [q-bio], Quantitative Trait Loci, Datasets as Topic, Gene Expression, Context (language use), QH426-470, Immunoglobulin E, Polymorphism, Single Nucleotide, 03 medical and health sciences, Social genetic effects, Genetic Heterogeneity, Mice, 0302 clinical medicine, Stress, Physiological, Genetics, Animals, Humans, Genotip, Biology (General), Genetic association, Wound Healing, biology, Genetic heterogeneity, Research, Receptor, EphA4, Genotype to phenotype, Phenotype, Human genetics, Fenotip, [SDV] Life Sciences [q-bio], Genòmica, 030104 developmental biology, Indirect genetic effects, Peer effects, biology.protein, Female, Gene-Environment Interaction, 030217 neurology & neurosurgery, Genètica
Abstract: Background: The phenotype of an individual can be affected not only by the individual's own genotypes, known as direct genetic effects (DGE), but also by genotypes of interacting partners, indirect genetic effects (IGE). IGE have been detected using polygenic models in multiple species, including laboratory mice and humans. However, the underlying mechanisms remain largely unknown. Genome-wide association studies of IGE (igeGWAS) can point to IGE genes, but have not yet been applied to non-familial IGE arising from "peers" and affecting biomedical phenotypes. In addition, the extent to which igeGWAS will identify loci not identified by dgeGWAS remains an open question. Finally, findings from igeGWAS have not been confirmed by experimental manipulation. Results: We leverage a dataset of 170 behavioral, physiological, and morphological phenotypes measured in 1812 genetically heterogeneous laboratory mice to study IGE arising between same-sex, adult, unrelated mice housed in the same cage. We develop and apply methods for igeGWAS in this context and identify 24 significant IGE loci for 17 phenotypes (FDR < 10%). We observe no overlap between IGE loci and DGE loci for the same phenotype, which is consistent with the moderate genetic correlations between DGE and IGE for the same phenotype estimated using polygenic models. Finally, we fine-map seven significant IGE loci to individual genes and find supportive evidence in an experiment with a knockout model that Epha4 gives rise to IGE on stress-coping strategy and wound healing. Conclusions: Our results demonstrate the potential for igeGWAS to identify IGE genes and shed light into the mechanisms of peer influence. Funding: AB was supported by a fellowship from the Wellcome Trust (105941/Z/14/Z). This work was partially supported by a pilot grant from NIH (P50DA037844 to AAP). Research in the Stegle lab is supported by core funding from EMBL, the BMBF, the Volkswagen Foundation, and the EU (ERC project DECODE 810296)
Published: 2021
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24. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Author: Nambot, Sophie, Faivre, Laurence, Mirzaa, Ghayda, Thevenon, Julien, Bruel, Ange-Line, Mosca-Boidron, Anne-Laure, Masurel-Paulet, Alice, Goldenberg, Alice, Le Meur, Nathalie, Charollais, Aude, Mignot, Cyril, Petit, Florence, Rossi, Massimiliano, Metreau, Julia, Layet, Valérie, Amram, Daniel, Boute-Bénéjean, Odile, Bhoj, Elizabeth, Cousin, Margot, Kruisselbrink, Teresa, Lanpher, Brendan, Klee, Eric, Fiala, Elise, Grange, Dorothy, Meschino, Wendy, Hiatt, Susan, Cooper, Gregory, Olivié, Hilde, Smith, Wendy, Dumas, Meghan, Lehman, Anna, Inglese, Cara, Nizon, Mathilde, Guerrini, Renzo, Vetro, Annalisa, Kaplan, Eitan, Miramar, Dolores, van Gils, Julien, Fergelot, Patricia, Bodamer, Olaf, Herkert, Johanna, Pajusalu, Sander, Õunap, Katrin, Filiano, James, Smol, Thomas, Piton, Amélie, Gérard, Bénédicte, Chantot-Bastaraud, Sandra, Bienvenu, Thierry, Li, Dong, Juusola, Jane, Devriendt, Koen, Bilan, Frederic, Poé, Charlotte, Chevarin, Martin, Jouan, Thibaud, Tisserant, Emilie, Rivière, Jean-Baptiste, Tran Mau-Them, Frédéric, Philippe, Christophe, Duffourd, Yannis, Dobyns, William, Hevner, Robert, Thauvin-Robinet, Christel, Couvet, Sandrine, 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, FHU TRANSLAD (CHU de Dijon), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Department of Pediatrics [Seattle], University of Washington [Seattle], Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique et embryologie médicales [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), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), 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), Genetics of Neurodevelopment (GENDEV), 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 Claude Bernard Lyon 1 (UCBL), Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Centre Hospitalier Intercommunal de Créteil (CHIC), Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics [Philadelphia, PA, USA], Mayo Clinic [Rochester], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Genetics [Saint-Louis], HudsonAlpha Institute for Biotechnology [Huntsville, AL], University Hospitals Leuven [Leuven], Maine Medical Center, University of British Columbia [Vancouver], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Meyer Children's Hospital [Florence, Italie], Università degli Studi di Firenze = University of Florence (UniFI), CHU Bordeaux [Bordeaux], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), University Medical Center Groningen [Groningen] (UMCG), University of Tartu, Dartmouth Hitchcock Medical Center [Lebanon, NH, USA] (DHMC), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], UF de Génétique chromosomique [CHU Trousseau], Service de Génétique et Biologie Moléculaires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), GeneDx [Gaithersburg, MD, USA], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, and 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)
Subjects: Proband, Candidate gene, INTELLECTUAL DISABILITY, MESH: Hippocampus, [SDV]Life Sciences [q-bio], MESH: Cognition, MESH: Neocortex, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Animals, MESH: Syndrome, Genetics (clinical), Genetics, PROGENITORS, biology, Phenotype, NEOCORTEX, [SDV] Life Sciences [q-bio], EXPRESSION, GENES, MESH: Mutation, MESH: T-Box Domain Proteins, MESH: Autistic Disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Article, REGION, MESH: Intellectual Disability, NEUROGENESIS, Dysgenesis, FEZF2, medicine, MESH: Mice, MESH: Adolescent, MESH: Humans, MUTATIONS, business.industry, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Autism, TBR1, business, Neurocognitive, MESH: Female
Abstract: International audience; TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.
Published: 2020
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25. Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

Author: Quentin Thomas, Marialetizia Motta, Thierry Gautier, Maha S. Zaki, Andrea Ciolfi, Julien Paccaud, François Girodon, Odile Boespflug-Tanguy, Thomas Besnard, Jennifer Kerkhof, Haley McConkey, Aymeric Masson, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Eva Trochu, Virginie Vignard, Fatima El It, Lance H. Rodan, Mohammad Ayman Alkhateeb, Rami Abou Jamra, Laurence Duplomb, Emilie Tisserant, Yannis Duffourd, Ange-Line Bruel, Adam Jackson, Siddharth Banka, Meriel McEntagart, Anand Saggar, Joseph G. Gleeson, David Sievert, Hyunwoo Bae, Beom Hee Lee, Kisang Kwon, Go Hun Seo, Hane Lee, Anjum Saeed, Nadeem Anjum, Huma Cheema, Salem Alawbathani, Imran Khan, Jorge Pinto-Basto, Joyce Teoh, Jasmine Wong, Umar Bin Mohamad Sahari, Henry Houlden, Kristina Zhelcheska, Melanie Pannetier, Mona A. Awad, Marion Lesieur-Sebellin, Giulia Barcia, Jeanne Amiel, Julian Delanne, Christophe Philippe, Laurence Faivre, Sylvie Odent, Aida Bertoli-Avella, Christel Thauvin, Bekim Sadikovic, Bruno Reversade, Reza Maroofian, Jérôme Govin, Marco Tartaglia, Antonio Vitobello, 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), 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), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), CHU Pontchaillou [Rennes], 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 ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), and the European Union through the FEDER programs, EJP-RD (NSEuroNET), AIRC (IG21614), and Italian Ministry of Health (5x1000). Sequencing for individual 15 was funded by the Institute for Information and Communications Technology Promotion (IITP) grant from the Korean government (MSIT) (2018-0-00861, Intelligent SW Technology Development for Medical Data Analysis). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome (www.ddduk.org/access.html).55 This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by individuals and collected by the National Health Service as part of their care and support. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 779257.
Subjects: Cell Nucleus, [SDV.GEN]Life Sciences [q-bio]/Genetics, DNA methylation, Loss of Heterozygosity, facial dysmorphism, neurodevelopmental disorder, Chromatin, Musculoskeletal Abnormalities, transcriptomics, translocon dysfunction, Pelger-Huët anomaly, intellectual disability, Genetics, LBR, Humans, TMEM147, nuclear envelope instability, Child, Pelger-Huet Anomaly, Genetics (clinical)
Abstract: International audience; The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.
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25 results on '"Institut Agro Dijon"'

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

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

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

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

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

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10. Genetic analysis of global faba bean diversity, agronomic traits and selection signatures

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12. Should we screen for colorectal cancer in people aged 75 and over? A systematic review - collaborative work of the French geriatric oncology society (SOFOG) and the French federation of digestive oncology (FFCD)

13. Limited Transmission of Klebsiella pneumoniae among Humans, Animals, and the Environment in a Caribbean Island, Guadeloupe (French West Indies)

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21. Genome sequencing for genetics diagnosis of patients with intellectual disability: the DEFIDIAG study

22. A positively-selected MAGEE2 LoF allele is associated with sexual dimorphism in human brain size, and shows similar phenotypes in Magee2 null mice

23. Dissecting indirect genetic effects from peers in laboratory mice

24. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

25. Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

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25 results on '"Institut Agro Dijon"'

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