Author: "Christèle Dubourg" - Searchworks@Jio Institute Digital Library Search Results

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116 results on '"Christèle Dubourg"'

1. Impact of Sonic Hedgehog‐dependent sphenoid bone defect on craniofacial growth

Author: Hélène Guyodo, Aurélie Rizzo, Farah Diab, Fanny Noury, Svetlana Mironov, Marie deTayrac, Véronique David, Sylvie Odent, Christèle Dubourg, and Valérie Dupé
Subjects: basisphenoid bone, hypomorphic mouse model, intersphenoid synchondrosis, sonic hedgehog, Dentistry, RK1-715
Abstract: Abstract Objectives The main objective of this study was to evaluate how an apparently minor anomaly of the sphenoid bone, observed in a haploinsufficient mouse model for Sonic Hedgehog (Shh), affects the growth of the adult craniofacial region. This study aims to provide valuable information to orthodontists when making decisions regarding individuals carrying SHH mutation. Materials and Methods The skulls of embryonic, juvenile and adult mice of two genotypes (Shh heterozygous and wild type) were examined and measured using landmark‐based linear dimensions. Additionally, we analysed the clinical characteristics of a group of patients and their relatives with SHH gene mutations. Results In the viable Shh+/− mouse model, bred on a C57BL/6J background, we noted the presence of a persistent foramen at the midline of the basisphenoid bone. This particular anomaly was attributed to the existence of an ectopic pituitary gland. We discovered that this anomaly led to premature closure of the intrasphenoidal synchondrosis and contributed to craniofacial deformities in adult mice, including a longitudinally shortened skull base. This developmental anomaly is reminiscent of that commonly observed in human holoprosencephaly, a disorder resulting from a deficiency in SHH activity. However, sphenoid morphogenesis is not currently monitored in individuals carrying SHH mutations. Conclusion Haploinsufficiency of Shh leads to isolated craniofacial skeletal hypoplasia in adult mouse. This finding highlights the importance of radiographic monitoring of the skull base in all individuals with SHH gene mutations.
Published: 2024
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2. O07: Haploinsufficiency of EIF3A and EIF3B cause a clinically variable phenotype characterized by neurodevelopmental abnormalities and congenital heart defects

Author: Cherith Somerville, Ersa Erkut, Marci Schwartz, Xin Chen, Roozbeh Manshaei, Qiliang Ding, Karin Diderich, Lisa Herzig, Bri Dingmann, Chloe Quelin, Véronique Pingault, Christèle Dubourg, Joana Rosmaninho Salgado, Sérgio Sousa, Daniel Koboldt, Rachel Gosselin, Kim McBride, Maria Arvio, Irma Järvelä, Isabelle Schrauwen, Laura Conlin, Cara Skraban, Sara Reichert, Jacqueline Leonard, Emma Bedoukian, Raymond Kim, Ian Scott, and Rebekah Jobling
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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3. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

Author: Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Julien Thevenon, Hana Safraou, Thomas Besnard, Alice Goldenberg, Benjamin Cogné, Bertrand Isidor, Julian Delanne, Arthur Sorlin, Sébastien Moutton, Mélanie Fradin, Christèle Dubourg, Magali Gorce, Dominique Bonneau, Salima El Chehadeh, François-Guillaume Debray, Martine Doco-Fenzy, Kevin Uguen, Nicolas Chatron, Bernard Aral, Nathalie Marle, Paul Kuentz, Anne Boland, Robert Olaso, Jean-François Deleuze, Damien Sanlaville, Patrick Callier, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, and Antonio Vitobello
Subjects: genome sequencing, RNA-seq, optical genome mapping, long-read sequencing, clinical diagnoses, Biology (General), QH301-705.5
Abstract: Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches.Methods: In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%–9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%–6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis.Results: SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization.Conclusion: Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.
Published: 2023
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4. A Robust and Fast/Multiplex Pharmacogenetics Assay to Simultaneously Analyze 17 Clinically Relevant Genetic Polymorphisms in CYP3A4, CYP3A5, CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, and VKORC1 Genes

Author: Camille Tron, Régis Bouvet, Marie-Clémence Verdier, Fabien Lamoureux, Benjamin Hennart, Christèle Dubourg, Eric Bellissant, and Marie-Dominique Galibert
Subjects: pharmacogenetics, panel, multiplex, CYP450, personalized medicine, Medicine, Pharmacy and materia medica, RS1-441
Abstract: In the field of pharmacogenetics, the trend is to analyze a panel of several actionable genetic polymorphisms. It may require the use of high-throughput sequencing which demands expensive reagents/instruments and specific skills to interpret results. As an alternative, the aim of this work was to validate an easy, fast, and inexpensive multiplex pharmacogenetics assay to simultaneously genotype a panel of 17 clinically actionable variants involved in drug pharmacokinetics/pharmacodynamics. We designed primers to perform a multiplex PCR assay using a single mix. Primers were labeled by two fluorescent dye markers to discriminate alleles, while the size of the PCR fragments analyzed by electrophoresis allowed identifying amplicon. Polymorphisms of interest were CYP3A4*22, CYP3A5*3, CYP1A2*1F, CYP2C9*2-*3, CYP2C19*2-*3-*17, VKORC1-1639G > A, ABCB1 rs1045642-rs1128503-rs2229109-rs2032582, and CYP2D6*3-*4-*6-*9. The assay was repeatable and a minimum quantity of 10 ng of DNA/ sample was needed to obtain accurate results. The method was applied to a validation cohort of 121 samples and genotyping results were consistent with those obtained with reference methods. The assay was fast and cost-effective with results being available within one working-day. This robust assay can easily be implemented in laboratories as an alternative to cumbersome simplex assays or expensive multiplex approaches. Together it should widespread access to pharmacogenetics in clinical routine practice.
Published: 2022
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5. Incidental diagnosis of mucopolysaccharidosis type I in an infant with chronic intestinal pseudoobstruction by exome sequencing

Author: Auriane Cospain, Christèle Dubourg, Swellen Gastineau, Samia Pichard, Virginie Gandemer, Jacinthe Bonneau, Marie de Tayrac, Caroline Moreau, Sylvie Odent, Laurent Pasquier, Lena Damaj, and Alinoë Lavillaureix
Subjects: Mucopolysaccharidosis type I, Hurler-Scheie disease, Exome sequencing, Chronic intestinal pseudoobstruction, Incidental finding, MYH11, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Chronic intestinal pseudoobstruction (CIPO) is a severe form of intestinal dysmotility, and patients often undergo iterative abdominal surgeries and require parenteral nutrition. Several genes are known to be responsible for this pathology, including ACTG2 (autosomal dominant) and MYH11 (autosomal recessive).We report the first case of unexpected trio medical exome sequencing diagnosis of mucopolysaccharidosis type I (MPS-I) in a patient with an early CIPO. There was no clinical suspicion of MPS-I at the time of the prescription. It allowed biochemical confirmation of MPS-I, expert clinical evaluation and early treatment. Enzyme replacement therapy (ERT) with laronidase was started at 9 months old, and hematopoietic stem cell transplantation was carried out at 10 months and a half. The patient also had a 1.7 mb heterozygous deletion in chromosomal region 16p13.11p12.3, comprising several genes, including MYH11, paternally inherited. Her father has no symptoms of CIPO or other digestive symptoms. One previous association of CIPO and MPS-I was reported in 1986. Moreover, the number of incidental findings of inherited metabolic disorders with therapeutic impact will inevitably increase as pangenomic analyses become cheaper and easily available.
Published: 2020
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6. Early care of N-acetyl glutamate synthase (NAGS) deficiency in three infants from an inbred family

Author: Katell Peoc'h, Léna Damaj, Romain Pelletier, Charles Lefèvre, Christèle Dubourg, Marie-Christine Denis, Claude Bendavid, Sylvie Odent, and Caroline Moreau
Subjects: Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: N-acetyl glutamate synthase (NAGS) deficiency is the rarest urea cycle defect presenting as neonatal onset life-threatening hyperammonemia. We report here a family history of severe NAGS deficiency: after the index-case with severe hyperammonemia, one patient benefited from antenatal diagnosis, and from primary care at birth, another one was diagnosed at 2-days and immediately treated with carbaglumic-acid. Finally, we report excellent tolerance to long-term carbaglumic-acid treatment, with no side effects, and healthy neurological and psychomotor development. Keywords: N-acetylglutamate synthase deficiency, Urea cycle defect, Hyperammonemia, Carbaglumic acid, Prenatal diagnosis
Published: 2020
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7. Homozygous STIL mutation causes holoprosencephaly and microcephaly in two siblings.

Author: Charlotte Mouden, Marie de Tayrac, Christèle Dubourg, Sophie Rose, Wilfrid Carré, Houda Hamdi-Rozé, Marie-Claude Babron, Linda Akloul, Bénédicte Héron-Longe, Sylvie Odent, Valérie Dupé, Régis Giet, and Véronique David
Subjects: Medicine, Science
Abstract: Holoprosencephaly (HPE) is a frequent congenital malformation of the brain characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been identified in HPE patients that account for only 30% of HPE cases, suggesting the existence of other HPE genes. Data from homozygosity mapping and whole-exome sequencing in a consanguineous Turkish family were combined to identify a homozygous missense mutation (c.2150G>A; p.Gly717Glu) in STIL, common to the two affected children. STIL has a role in centriole formation and has previously been described in rare cases of microcephaly. Rescue experiments in U2OS cells showed that the STIL p.Gly717Glu mutation was not able to fully restore the centriole duplication failure following depletion of endogenous STIL protein indicating the deleterious role of the mutation. In situ hybridization experiments using chick embryos demonstrated that expression of Stil was in accordance with a function during early patterning of the forebrain. It is only the second time that a STIL homozygous mutation causing a recessive form of HPE was reported. This result also supports the genetic heterogeneity of HPE and increases the panel of genes to be tested for HPE diagnosis.
Published: 2015
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8. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders

Author: Thomas Husson, François Lecoquierre, Gaël Nicolas, Anne-Claire Richard, Alexandra Afenjar, Séverine AUDEBERT-BELLANGER, Catherine Badens, Frédéric Bilan, Varoona Bizaoui, Anne Boland, Marie-Noelle Bonnet-Dupeyron, Elise Brischoux-Boucher, Céline Bonnet, Marie Bournez, Odile Boute, Perrine Brunelle, Roseline Caumes, Perrine Charles, Nicolas Chassaing, Nicolas Chatron, Benjamin Cogné, Estelle Colin, Valérie Cormier-Daire, Rodolphe Dard, Benjamin Dauriat, Julian Delanne, Jean-François Deleuze, Florence Demurger, Anne-Sophie Denommé-Pichon, Christel Depienne, Anne Dieux Coeslier, Christèle Dubourg, Patrick Edery, salima EL CHEHADEH, Laurence Faivre, Mélanie FRADIN, Aurore Garde, David Geneviève, Brigitte Gilbert-Dussardier, Cyril Goizet, Alice Goldenberg, Evan Gouy, Anne-Marie Guerrot, Anne Guimier, Ines HARZALLAH, Delphine Héron, Bertrand Isidor, Xavier Le Guillou Horn, Boris Keren, Alma Kuechler, Elodie Lacaze, Alinoë Lavillaureix, Daphné Lehalle, Gaetan Lesca, James Lespinasse, Jonathan Levy, Stanislas Lyonnet, Godelieve Morel, Nolwenn Jean Marçais, Sandrine Marlin, Luisa Marsili, Cyril Mignot, Sophie Nambot, Mathilde Nizon, Robert Olaso, Laurent PASQUIER, Laurine Perrin, Florence Petit, Amélie Piton, Fabienne Prieur, Audrey Putoux, Marc Planes, Sylvie Odent, Chloé Quelin, Sylvia Quemener, Mélanie Rama, Marlène RIO, Massimiliano Rossi, Elise Schaefer, Sophie Rondeau, Pascale SAUGIER-VEBER, Thomas Smol, Sabine Sigaudy, Renaud TOURAINE, Frédéric Tran-Mau-Them, Aurélien Trimouille, Clémence Vanlerberghe, Valérie Vantalon, Gabriella Vera, Marie Vincent, Alban Ziegler, Olivier Guillin, Dominique Campion, and Camille Charbonnier
Abstract: Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 102 carriers of (likely) pathogenic variants in ten different genes, 58 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached less than 40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70%-100% sensibility at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.
Published: 2023

9. Fetal Description of the Pancreatic Agenesis and Holoprosencephaly Syndrome Associated to a Specific CNOT1 Variant

Author: Auriane Cospain, Marie Faoucher, Aurélie Cauchois, Wilfrid Carre, Chloé Quelin, Christèle Dubourg, CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Institut de Génétique et Développement de Rennes (IGDR), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: musculoskeletal diseases, hypoplasia, [SDV.GEN]Life Sciences [q-bio]/Genetics, holoprosencephaly, fetal autopsy, congenital malformation, Pediatrics, Perinatology and Child Health, CNOT1, General Medicine, pancreas agenesis, post-mortem examination, Pathology and Forensic Medicine
Abstract: International audience; Holoprosencephaly (HPE) is a clinically and genetically heterogeneous disease, which can be associated with various prenatal comorbidities not always detectable on prenatal ultrasound. We report on the case of a foetus carrying a semi-lobar HPE diagnosed at ultrasound, for which a fetal autopsy and a whole exome sequencing were performed following a medical termination of pregnancy. Neuropathological examination confirmed the semi-lobar HPE and general autopsy disclosed a total pancreas agenesis. Whole exome sequencing found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo in the foetus. The same variant was previously reported in 5 unrelated children. All individuals had HPE, and 4 out of 5 presented endo- and exocrine pancreatic insufficiency or total pancreas agenesis. CNOT1 encodes a subunit of the CCRN4-NOT complex, expressed at the early stage of embryonic development. This report is the first fetal description of the phenotype associating HPE and pancreatic agenesis linked to the recurrent CNOT1 missense c.1603C>T, p.(Arg535Cys). This finding strengthens the hypothesis of a specific recurrent variant associated with a particular phenotype of HPE and pancreas agenesis. The fetal autopsy that revealed the pancreas agenesis was crucial in guiding the genetic diagnosis and enabling accurate genetic counselling.
Published: 2022

10. Child with a mild CHIME syndrome phenotype and carrying a novel p.(Asp52Asn) PIGL pathogenic variant in association with the previously reported p.(Leu167Pro) variant: A case report

Author: Marion Rolland, Christèle Dubourg, Auriane Cospain, Catherine Droitcourt, Laurent Pasquier, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), This research did not receive any specific funding from agencies or organizations in the public, commercial, or not-for-profit sectors., and Chard-Hutchinson, Xavier
Subjects: PIGL, [SDV] Life Sciences [q-bio], [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV]Life Sciences [q-bio], Pediatrics, Perinatology and Child Health, neuroectodermal disorder, case report, CHIME syndrome, [SDV.GEN] Life Sciences [q-bio]/Genetics, Dermatology
Abstract: International audience; Coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME) syndrome is a very rare autosomal recessive neuroectodermal disorder related to PIGL gene mutations. Here, we report a patient who showed an initial delay in psychomotor development and skin abnormalities consistent with CHIME syndrome but with atypical clinical features and laboratory findings. In line with our clinical suspicion, the c.500T>C, p.(Leu167Pro) variant (found in all the previously described cases of CHIME syndrome) was found on the paternal allele. A novel “likely pathogenic” PIGL missense variant (c.154G>A, p.(Asp52Asn)) was detected on the maternal allele. This case provides new insights into the clinical spectrum of CHIME syndrome and highlights the potential for phenotypic/genotypic variations.
Published: 2022

11. Gene Editing Corrects In Vitro a G > A GLB1 Transition from a GM1 Gangliosidosis Patient

Author: Delphine Leclerc, Louise Goujon, Sylvie Jaillard, Bénédicte Nouyou, Laurence Cluzeau, Léna Damaj, Christèle Dubourg, Amandine Etcheverry, Thierry Levade, Roseline Froissart, Stéphane Dréano, Xavier Guillory, Leif A Eriksson, Erika Launay, Frédéric Mouriaux, Marc-Antoine Belaud-Rotureau, Sylvie Odent, David Gilot, 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], École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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 ), Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hospices Civils de Lyon (HCL), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and University of Gothenburg (GU)
Subjects: [SDV]Life Sciences [q-bio], Genetics, Original Research, Biotechnology
Abstract: International audience; Ganglioside-monosialic acid (GM1) gangliosidosis, a rare autosomal recessive disorder, is frequently caused by deleterious single nucleotide variants (SNVs) in GLB1 gene. These variants result in reduced β-galactosidase (β-gal) activity, leading to neurodegeneration associated with premature death. Currently, no effective therapy for GM1 gangliosidosis is available. Three ongoing clinical trials aim to deliver a functional copy of the GLB1 gene to stop disease progression. In this study, we show that 41% of GLB1 pathogenic SNVs can be replaced by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring therapeutic levels of β-gal activity. Off-target DNA analysis did not detect off-target editing activity in treated patient’s cells, except a bystander edit without consequences on β-gal activity based on 3D structure bioinformatics predictions. Altogether, our results suggest that gene editing might be an alternative strategy to cure GM1 gangliosidosis.
Published: 2023

12. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Author: Marjolaine Willems, Benjamin Durand, Boris Keren, Kristina Pilekær Sørensen, Rosanna Weksberg, Magalie Barth, Christina Fagerberg, Cyril Mignot, Laurence Perrin, Lucas Bronicki, Nathalie Drouot, Imene Boujelbene, Marc Abramowicz, Maria Kibaek, Bertrand Isidor, Thierry Bienvenu, Mathilde Nizon, Perrine Charles, Laurent Pasquier, Yann Herault, Marie Christine Birling, Bruno Delobel, Michel Guipponi, Lydie Burglen, Mélanie Fradin, Anne Sophie Denommé, Florence Demurger, Benjamin Cogné, Sébastien Moutton, Allan Bayat, Frederic Tran Mau Them, Christèle Dubourg, Alice Goldenberg, Christine Francannet, Jean-Louis Mandel, Laurence Faivre, Jérémie Courraud, Anne Marie Guerrot, Julia Metreau, Loréline Genschik, Bénédicte Demeer, Marie Vincent, Mathilde Renaud, Julien Thevenon, Sandrine Passemard, Christine Coubes, Amélie Piton, David Geneviève, Maria del Mar Muniz Moreno, Bénédicte Gérard, Estelle Colin, Valérie Layet, Michèle Mathieu-Dramard, Salima El Chehadeh, Katrine M Johannesen, Julie D. Thompson, Cathrine Elisabeth Tronhjem, Pascale Saugier, Elise Schaefer, Eric Chater-Diehl, Séverine Drunat, Rikke S. Møller, Paul Kuentz, Claire Feger, Albert David, Antonio Vitobello, Marlène Rio, Khaoula Khachnaoui, Joane Svane, Stéphane Auvin, 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), The Hospital for sick children [Toronto] (SickKids), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpital Universitaire de Genève, Children's hospital of Eastern Ontario Research Institute [Ottawa, canada] (CHEO), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Hôpital Robert Debré, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], CHU Clermont-Ferrand, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Southern Denmark (SDU), Odense University Hospital (OUH), CHU Amiens-Picardie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Odense University Hospital [Odense, Denmark], Centre Hospitalier Universitaire [Grenoble] (CHU), Groupe Hospitalier du Havre, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut Clinique de la Souris, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Hôpital Cochin [AP-HP], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), University of Toronto, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-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 (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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 ), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Agence de Biomédecine, Fondation APLM, Fondation Maladies Rares and Fondation Jérome Lejeune, univOAK, Archive ouverte, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], DYRK1A, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Protein Serine-Threonine Kinases, Biology, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, medicine, Animals, Humans, Missense mutation, Kinase activity, Gene, Genetics (clinical), Cellular localization, 030304 developmental biology, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Protein-Tyrosine Kinases, medicine.disease, Phenotype, Human genetics, 3. Good health, 030220 oncology & carcinogenesis, Microcephaly
Abstract: Purpose: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics. Methods: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature. Results: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice. Conclusion: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene. Graphic abstract: [Figure not available: see fulltext.]
Published: 2021

13. <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

14. A Robust and Fast/Multiplex Pharmacogenetics Assay to Simultaneously Analyze 17 Clinically Relevant Genetic Polymorphisms in CYP3A4, CYP3A5, CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, and VKORC1 Genes

Author: Galibert, Camille Tron, Régis Bouvet, Marie-Clémence Verdier, Fabien Lamoureux, Benjamin Hennart, Christèle Dubourg, Eric Bellissant, and Marie-Dominique
Subjects: pharmacogenetics, panel, multiplex, CYP450, personalized medicine
Abstract: In the field of pharmacogenetics, the trend is to analyze a panel of several actionable genetic polymorphisms. It may require the use of high-throughput sequencing which demands expensive reagents/instruments and specific skills to interpret results. As an alternative, the aim of this work was to validate an easy, fast, and inexpensive multiplex pharmacogenetics assay to simultaneously genotype a panel of 17 clinically actionable variants involved in drug pharmacokinetics/pharmacodynamics. We designed primers to perform a multiplex PCR assay using a single mix. Primers were labeled by two fluorescent dye markers to discriminate alleles, while the size of the PCR fragments analyzed by electrophoresis allowed identifying amplicon. Polymorphisms of interest were CYP3A4*22, CYP3A5*3, CYP1A2*1F, CYP2C9*2-*3, CYP2C19*2-*3-*17, VKORC1-1639G > A, ABCB1 rs1045642-rs1128503-rs2229109-rs2032582, and CYP2D6*3-*4-*6-*9. The assay was repeatable and a minimum quantity of 10 ng of DNA/ sample was needed to obtain accurate results. The method was applied to a validation cohort of 121 samples and genotyping results were consistent with those obtained with reference methods. The assay was fast and cost-effective with results being available within one working-day. This robust assay can easily be implemented in laboratories as an alternative to cumbersome simplex assays or expensive multiplex approaches. Together it should widespread access to pharmacogenetics in clinical routine practice.
Published: 2022
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15. Gene editing is suitable to treat GM1 Gangliosidosis: a proof-of-concept study

Author: Delphine Leclerc, Louise Goujon, Sylvie Jaillard, Bénédicte Nouyou, Laurence Cluzeau, Léna Damaj, Christèle Dubourg, Amandine Etcheverry, Thierry Levade, Roseline Froissart, Stéphane Dréano, Xavier Guillory, Leif A Eriksson, Erika Launay, Frédéric Mouriaux, Marc-Antoine Belaud-Rotureau, Sylvie Odent, and David Gilot
Abstract: Ganglioside-monosialic acid (GM1) gangliosidosis, a rare autosomal recessive disorder, is frequently caused by deleterious single nucleotide variants (SNVs) in GLB1 gene. These variants result in reduced β-galactosidase (β-gal) activity, leading to neurodegeneration associated with premature death. Currently, no effective therapy for GM1 gangliosidosis is available. Three ongoing clinical trials aim to deliver a functional copy of the GLB1 gene to stop disease progression. Here, we show that 41% of GLB1 pathogenic SNVs might be cured by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring a therapeutic level of β-gal activity. Unbiased off-target DNA analysis did not detect off-target editing activity in treated patient’s cells except a bystander edit without consequences on β-gal activity. Altogether our results suggest that gene editing is an alternative strategy to cure GM1 gangliosidosis, by correcting the root cause of disease and avoiding repetitive adeno-associated virus injections.
Published: 2022

16. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author: Ashley N. Sigafoos, Salima El Chehadeh, Marcia C. Willing, Ela Akay, Florian Cherik, Anne-Marie E. Goyette, Vinodh Narayanan, Diane Masser-Frye, Catherine Karimov, Rhonda E. Schnur, Rebekah Bressi, Rhys H. Thomas, Gary D. Clark, Tina Barbaro-Dieber, Jill A. Rosenfeld, Carlos A. Bacino, Maria J. Guillen Sacoto, Laura Russell, Kristin Lindstrom, Caroline Schluth-Bolard, Xia Wang, Yvonne Hilhorst-Hofstee, Marcelo Vargas, Zehua Zhu, Ash Zawerton, Boris Keren, Mariëtte J.V. Hoffer, Isabelle Marey, Alice Poisson, Daphné Lehalle, Maries Joseph, Gaetan Lesca, Simon Zwolinski, Laurence Perrin, Rhoda Akilapa, Emilia K. Bijlsma, Christel Depienne, Amélie Piton, Claire G. Salter, Lucie Dupuis, Daryl A. Scott, Jolien S. Klein Wassink-Ruiter, Benjamin Cogné, Mathilde Nizon, Richard Chang, Kirsty McWalter, Myriam Srour, Perrine Charles, Anne-Claude Tabet, Natalie Canham, Sylvie Odent, Caroline Nava, Karl J. Clark, Elizabeth J. Bhoj, Jonathan Levy, Keri Ramsey, Yves Alembik, Lucia Ortega, Sophie Dupuis-Girod, Shoji Ichikawa, Christine Francannet, Marta Bertoli, Christèle Dubourg, Eric W. Klee, Ange-Line Bruel, Sebastien Moutton, Emily Fassi, Anthony Vandersteen, Abdul Haseeb, Antonina Wojcik, Patrick R. Blackburn, Lynne M. Bird, Patrick Rump, Véronique Lefebvre, Alma Kuechler, Sophie Nambot, Keren Machol, Cyril Mignot, Andreas Hartmann, Rossana Sanchez Russo, Erica H. Gerkes, Sylvie Jaillard, Roberto Mendoza-Londono, Trevor Cole, Pauline Monin, Cleveland Clinic, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-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 Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, This research was funded in part by the Agence Nationale de la Recherche and European High-Functioning Autism Network (ANR EUHFAUTISM), the Assistance Publique–Hôpitaux de Paris (AP-HP), the Institut National de la Santé et de la Recherche Médicale (INSERM), the BioPsy labex (to Christel Depienne and C.N.) and the Association Française du Syndrome Gilles de la Tourette (AFSGT) to Christel Depienne. It was also funded by the Cleveland Clinic Lerner Research Institute (LRI Chair’s Innovative Research Award to V.L.), and by Harper’s Quest and the LAMSHF Syndrome Research Fund (donations to V.L.) and the Center for Individualized Medicine, Mayo Clinic. This study makes use of data generated by the DECIPHER community and the Deciphering Developmental Disorders (DDD) Study, which is funded by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network., We thank the patients and their families for their participation in this study, and the C4RCD Research Group (Newell Belnap, Amanda Courtright, Ana Claasen, David Craig, Matt Huentelman, Madison LaFleur, Sampathkumar Rangasamy, Ryan Richholt, Isabelle Schrauwen, Ashley L. Siniard, and Szabolics Szelinger) for providing clinical information on patient P18., Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-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 d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Medizin, Haploinsufficiency, L-SOX5, VARIANTS, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics, Pediatric, Genetics & Heredity, 0303 health sciences, Pedigree, FAMILY, DNA-Binding Proteins, developmental delay, TRANSCRIPTION FACTORS, Phenotype, intellectual disability, Child, Preschool, missense variants, Female, SOXD Transcription Factors, Adult, EXPRESSION, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Mutation, Missense, autism, Cell fate determination, Biology, LONG FORM, SEQUENCE, Article, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, CARTILAGE, Intellectual Disability, medicine, Animals, Humans, Language Development Disorders, Genetic Predisposition to Disease, Preschool, Transcription factor, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, Human Genome, Infant, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, Deciphering Developmental Disorder Study, Mutation, Autism, epilepsy, Missense, 030217 neurology & neurosurgery, GENERATION
Abstract: International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
Published: 2020

17. Role of Chromosomal Imbalances in the Pathogenesis of DSD: A Retrospective Analysis of 4657 Prenatal Samples

Author: Laura Mary, Melanie Fradin, Laurent Pasquier, Chloé Quelin, Philippe Loget, Maëla Le Lous, Gwénaëlle Le Bouar, Sylvie Nivot-Adamiak, Anna Lokchine, Christèle Dubourg, Vincent Jauffret, Bénédicte Nouyou, Catherine Henry, Erika Launay, Sylvie Odent, Sylvie Jaillard, and Marc-Antoine Belaud-Rotureau
Subjects: History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published: 2022

18. DNA methylation episignature in Gabriele-de Vries syndrome

Author: Florian Cherik, Jack Reilly, Jennifer Kerkhof, Michael Levy, Haley McConkey, Mouna Barat-Houari, Kameryn M. Butler, Christine Coubes, Jennifer A. Lee, Gwenael Le Guyader, Raymond J. Louie, Wesley G. Patterson, Matthew L. Tedder, Mads Bak, Trine Bjørg Hammer, William Craigen, Florence Démurger, Christèle Dubourg, Mélanie Fradin, Rachel Franciskovich, Eirik Frengen, Jennifer Friedman, Nathalie Ruiz Palares, Maria Iascone, Doriana Misceo, Pauline Monin, Sylvie Odent, Christophe Philippe, Flavien Rouxel, Veronica Saletti, Petter Strømme, Perla Cassayre Thulin, Bekim Sadikovic, David Genevieve, CHU Clermont-Ferrand, University of Western Ontario (UWO), London Health Sciences Center (LHSC), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), The Greenwood Genetic Center, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Baylor College of Medicine (BCM), Baylor University, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), 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], Oslo University Hospital [Oslo], University of California [San Diego] (UC San Diego), University of California (UC), Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', and University of Utah
Subjects: Male, Gabriele-de Vries syndrome, Genome, Phenotype, Neurodevelopmental Disorders, [SDV]Life Sciences [q-bio], Intellectual Disability, Humans, Epigenetics, Syndrome, DNA Methylation, YY1, Genetics (clinical)
Abstract: International audience; PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance.
Published: 2021

19. Case report: Antenatal diagnostic of a polymalformative syndrome due to biallelic BRCA2 mutations

Author: Aude Anquetil, Anne Bazin, Fabien Guimiot, Laurent Mandelbrot, Olivier Picone, Laurent Gavard, Suonavy Khung Savatovsky, Christèle Dubourg, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Pontchaillou [Rennes], 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), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Medicine (General), Pediatrics, medicine.medical_specialty, endocrine system diseases, Genetic counseling, [SDV]Life Sciences [q-bio], education, Prenatal diagnosis, Case Report, Case Reports, 03 medical and health sciences, R5-920, 0302 clinical medicine, Fanconi anemia, medicine, Genetics, Polymalformative symdrome, skin and connective tissue diseases, neoplasms, VACTERL‐H, 030304 developmental biology, 0303 health sciences, business.industry, ultrasound, General Medicine, medicine.disease, BRCA2, female genital diseases and pregnancy complications, 3. Good health, 030220 oncology & carcinogenesis, Medicine, business
Abstract: Testing the partner of a BRCA2 carrier must always be discussed. If both members of the couple are BRCA2 carriers, they should be informed about the high risks of polymalformative syndromes.
Published: 2021

20. Phénotype prénatal des microduplications 22q11 : description de 12 nouveaux cas et Revue de la littérature

Author: Laura Mary, Alinoë Lavillaureix, Adélie Perrot, Philippe Loget, Erika Launay, Anne-Sophie Leborgne, Florence Demurger, Mélanie Fradin, Gwenaelle Le Bouar, Chloé Quélin, Christèle Dubourg, Laurent Pasquier, Sylvie Odent, Marc-Antoine Belaud-Rotureau, and Sylvie Jaillard
Subjects: Anatomy
Published: 2022

21. De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Author: Elysa J. Marco, Heather C Mefford, Stacey McGee, Christèle Dubourg, Edmund Cauley, Randi J Hagerman, Maria J. Nabais Sá, Bert B.A. de Vries, Rüdiger Lorenz, Elizabeth E. Palmer, Michael J. Parker, Arjan P.M. de Brouwer, Hester Y. Kroes, M. Chiara Manzini, Abbey A. Scott, Tara Montgomery, Naama Orenstein, Jeanne Amiel, Delphine Héron, Leonie A. Menke, Jonathan Berg, Sylvie Odent, Rachel Harrison, Philip J. Jensik, Rani Sachdev, Miranda Splitt, Tyler Mark Pierson, Jan Maarten Cobben, Ehsan Ghayoor Karimiani, Anneke T. Vulto-vanSilfhout, Roberto Colombo, Nayana Lahiri, Julian A. Martinez-Agosto, Evan P. McNeil, Boris Keren, John M. Graham, Chanika Phornphutkul, Reza Maroofian, Radboud University Medical Center [Nijmegen], Southern Illinois University [Carbondale] (SIU), Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, St George's, University of London, Geisel School of Medicine at Dartmouth, University Medical Center [Utrecht], University of California [Davis] (UC Davis), University of California, Nottingham University Hospitals NHS Trust, Northern Genetics Service, Newcastle University [Newcastle], University of New South Wales [Sydney] (UNSW), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, University of California [Los Angeles] (UCLA), Tel Aviv University [Tel Aviv], University of Dundee, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Amsterdam [Amsterdam] (UvA), Cedars-Sinai Medical Center, The George Washington University (GW), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Warren Alpert Medical School of Brown University, University of California (UC), Nottingham University Hospitals NHS Trust (NUH), Department of Pediatrics [Seattle, WA, USA], Tel Aviv University (TAU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 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 ), General Paediatrics, Paediatric Genetics, Amsterdam Reproduction & Development (AR&D), Sheffield Children's Hospital, St George‘s, University of London, University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], George Washington University (GW), and AMS - Sports
Subjects: Adult, Male, Microcephaly, Adolescent, phenotype, Developmental Disabilities, genotype, [SDV]Life Sciences [q-bio], Mutation, Missense, Biology, Young Adult, 03 medical and health sciences, Neurodevelopmental disorder, All institutes and research themes of the Radboud University Medical Center, Genotype, medicine, Humans, Exome, Language Development Disorders, Autistic Disorder, Allele, Child, Alleles, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 030305 genetics & heredity, medicine.disease, Phenotype, neurodevelopmental disorder, Human genetics, DEAF1, DNA-Binding Proteins, intellectual disability, Child, Preschool, Speech delay, Autism, Female, medicine.symptom, Transcription Factors
Abstract: International audience; Purpose To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. Methods We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype–phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. Results The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). Conclusion We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients. © 2019, American College of Medical Genetics and Genomics.
Published: 2019

22. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Author: Anne-Sophie Denommé, Christine Francannet, Loréline Genschik, Claire Feger, Maria Kibaek, Imene Boujelbene, Paul Kuentz, Michel Guipponi, Marie-Christine Birling, Sébastien Moutton, Allan Bayat, Frederic Tran Mau Them, Mathilde Renaud, Joane Svane, Yann Herault, Sandrine Passemard, Christèle Dubourg, Mélanie Fradin, Marjolaine Willems, Julien Thevenon, Rosanna Weksberg, Bertrand Isidor, David Geneviève, Benjamin Cogné, Magalie Barth, Laurence Faivre, Jérémie Courraud, Boris Keren, Albert David, Laurence Perrin, Anne-Marie Guerrot, Christine Coubes, Thierry Bienvenu, Alice Goldenberg, Bénédicte Gérard, Amélie Piton, Lucas Bronicki, Julia Metreau, Mathilde Nizon, Elise Schaefer, Eric Chater-Diehl, Maria del Mar Muniz Moreno, Bruno Delobel, Katrine M Johannesen, Florence Demurger, Nathalie Drouot, Marie Vincent, Antonio Vitobello, Kristina Pilekær Sørensen, Christina Fagerberg, Cyril Mignot, Estelle Colin, Valérie Layet, Michèle Mathieu-Dramard, Jean-Louis Mandel, Cathrine Elisabeth Tronhjem, Benjamin Durand, Pascale Saugier, Séverine Drunat, Rikke S. Møller, Perrine Charles, Lydie Burglen, Bénédicte Demeer, Salima El Chehadeh, Marc Abramowicz, Laurent Pasquier, and Julie D. Thompson
Subjects: Genetics, Neurodevelopmental disorder, DYRK1A, Intellectual disability, medicine, Missense mutation, Kinase activity, Biology, medicine.disease, Phenotype, Human genetics, Cellular localization
Abstract: ABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboringDYRK1Avariants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specificDYRK1Aclinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii)in vitrooverexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurringde novo.
Published: 2021

23. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author: Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, Ping Yee Billie Au, Boston Children's Hospital, University of Alberta, Universität Leipzig [Leipzig], Geneva University Hospital (HUG), Tel Aviv University [Tel Aviv], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Baylor College of Medicine (BCM), Baylor University, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CHU Pontchaillou [Rennes], 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), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Lausanne University Hospital, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Children’s Hospital of Philadelphia (CHOP ), Hospital Universitario La Paz, 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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Duke University [Durham], University of Kansas Medical Center [Lawrence], University of Missouri System, Children's Mercy Hospital [Kansas City], Weill Cornell Medicine [New York], University of Calgary, Research reported in this paper was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number(s) (U01HG007709 [Baylor College of Medicine] and U01HG007672 [Duke University to V.S.]). Additional funding for this project was under award number 1RO1HD090132-01A1 (Cornell University to G.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided by a Canadian Institutes of Health Research Grant (MOP-97988 to H.T.K.), and a Rowland and Muriel Haryett Fellowship (University of Alberta, to S.M.L.) and a fellowship from the Ministry of Education and Research of the Community of Madrid to M.P.M. (B2017/BMD-3721), and microgrant from the Rare Disease Foundation (P.Y.B.A. and H.T.K.). Sequencing and analysis was supported by the National Human Genome Research Institute grants UM1 HG008900 and R01 HG009141. K.A.D., B.C., and E.O. were supported the National Institute of Mental Health U01 MH119689., Universität Leipzig, Columbia University Medical Center (CUMC), Columbia University [New York], Tel Aviv University (TAU), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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 ), Unité de recherche de l'institut du thorax (ITX-lab), University of Kansas Medical Center [Kansas City, KS, USA], Weill Cornell Medicine [Cornell University], and Cornell University [New York]
Subjects: Ataxia, Calcium Channels, L-Type, Long QT syndrome, Timothy syndrome, Bioinformatics, Article, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual disability, medicine, Missense mutation, Humans, Autistic Disorder, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, Long QT Syndrome, Phenotype, Autism, Syndactyly, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Purpose:CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.Methods:We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.Results:Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.Conclusion:We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
Published: 2020

24. The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms

Author: Marie-France Portnoï, Alexandre Reymond, Sandra Chantot-Bastaraud, Giuliana Giannuzzi, Eleonora Porcu, Yvan Herenger, Flavie Ader, Tony Yammine, Patrick Edery, Pierre-Antoine Rollat-Farnier, Flavie Diguet, Laurence Faivre, Alice Masurel-Paulet, Nathalie Marle, Kévin Uguen, Claire Bardel, Julia Lauer Zillhardt, Alistair T. Pagnamenta, Nicolas Chatron, Jenny C. Taylor, Stéphanie Valence, Andrew O.M. Wilkie, Solveig Heide, Emilie Chopin, Fabienne Prieur, Nora Chelloug, Christèle Dubourg, Marlène Rio, Eduardo Calpena, Zohra-Lydia Bellil, Arthur Sorlin, Laurence Lohmann, Sylvie Jaillard, Alexandra Afenjar, Corinne Metay, Jean-Pierre Siffroi, Damien Sanlaville, Marie-Pierre Cordier, Boris Keren, Françoise Girard, Caroline Schluth-Bolard, Joris Andrieux, Samantha J. L. Knight, Reza Maroofian, James Lespinasse, Michèle Mathieu-Dramard, and Patrick Callier
Subjects: chemistry.chemical_compound, Chromothripsis, chemistry, Evolutionary biology, Premature chromosome condensation, Breakpoint, Chromosomal rearrangement, Biology, Gene, DNA, Sequence (medicine), Chromatin
Abstract: The rise of pangenomic molecular assays allowed uncovering complex rearrangements named chromoanagenesis that were hypothesized to result from catastrophic shattering events. Constitutional cases have typically been reported individually preventing identification of common features and uncovering the mechanisms at play. We characterized 20 new chromoanagenesis and discovered yet undescribed features. While literature differentiates chromothripsis and its shattering event repaired through non-homologous end joining from chromoanasynthesis born to aberrant replicative processes, we identified shattered chromosomes repaired through a combination of mechanisms. In particular, three samples present with “rearrangement hubs” comprising a fragmented kilobase-long sequence threaded throughout the rearrangement.To assess the mechanisms at play, we merged our data with those of 20 published constitutional complex chromosomal rearrangement cases. We evaluated if the distribution of their 1032 combined breakpoints was distinctive using bootstrap simulations and found that breakpoints tend to keep away from haplosensitive genes suggesting selective pressure. We then compared their distribution with that of 13,310 and 468 breakpoints of cancer complex chromosomal rearrangements and constitutional simple rearrangement samples, respectively. Both complex rearrangement groups showed breakpoint enrichment in late replicating regions suggesting similar origins for constitutional and cancer cases. Simple rearrangement breakpoints but not complex ones were depleted from lamina-associated domains (LADs), possibly as a consequence of reduced mobility of DNA ends bound to lamina.The enrichment of breakpoints in late-replicating chromatin for both constitutional and cancer chromoanagenesis provides an orthogonal support to the premature chromosome condensation hypothesis that was put forward to explain chromoanagenesis.
Published: 2020

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

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

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

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

27. GREB1L variants in familial and sporadic hereditary urogenital adysplasia and Mayer-Rokitansky-Kuster-Hauser syndrome

Author: Corinne Fasquelle, Karine Morcel, Anna Lehman, Christèle Dubourg, Jérôme Thiry, Véronique David, Claire Josse, Aimé Lumaka, Bouchra Boujemla, Daniel Guerrier, Vincent Bours, Elise Brischoux-Boucher, Adeline Jacquinet, Laurent Pasquier, Centre Hospitalier Universitaire de Liège (CHU-Liège), GIGA [Université Liège], Université de Liège, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), 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 Pontchaillou [Rennes], University of British Columbia (UBC), CHU Liège (FIRS), Fond Léon Frédéricq, Fonds De La Recherche Scientifique - FNRS, Service Public de Wallonie, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, Adult, Male, 46, XX Disorders of Sex Development, [SDV]Life Sciences [q-bio], urogenital abnormalities, Uterus, Penetrance, 030105 genetics & heredity, Kidney, Congenital Abnormalities, Cohort Studies, 03 medical and health sciences, hereditary renal agenesis, Fetus, Uterine malformation, Mullerian aplasia, Exome Sequencing, Genetics, Medicine, renal adysplasia, Humans, Mayer-Rokitansky-Kuster-Hauser Syndrome, Abnormalities, Multiple, Genetic Predisposition to Disease, Expressivity (genetics), Mullerian Ducts, Genetics (clinical), Exome sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, renal and Mullerian duct hypoplasia, Aplasia, uterine anomalies, medicine.disease, 3. Good health, GREB1L, Neoplasm Proteins, Bilateral Renal Agenesis, 030104 developmental biology, medicine.anatomical_structure, Mayer-Rokitansky-Kuster-Hauser syndrome, Female, business
Abstract: International audience; Congenital uterine anomalies (CUA) may have major impacts on the health and social well-being of affected individuals. Their expressivity is variable, with the most severe end of the spectrum being the absence of any fully or unilaterally developed uterus (aplastic uterus), which is a major feature in Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). So far, etiologies of CUA remain largely unknown. As reports of familial occurrences argue for strong genetic contributors in some cases, we performed whole exome sequencing in nine multiplex families with recurrence of uterine and kidney malformations, a condition called hereditary urogenital adysplasia. Heterozygous likely causative variants in the gene GREB1L were identified in four of these families, confirming GREB1L as an important gene for proper uterine and kidney development. The apparent mode of inheritance was autosomal dominant with incomplete penetrance. The four families included fetuses with uterovaginal aplasia and bilateral renal agenesis, highlighting the importance to investigate GREB1L in such phenotypes. Subsequent sequencing of the gene in a cohort of 68 individuals with MRKH syndrome or uterine malformation (mostly sporadic cases) identified six additional variants of unknown significance. We therefore conclude that heterozygous GREB1L variants contribute to MRKH syndrome and this probably requires additional genetic or environmental factors for full penetrance.
Published: 2020

28. Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

Author: Michelle Ware, Leslie Ratié, Sylvie Odent, Véronique David, Helene Guyodo, Maïlys Rupin, Artem Kim, Wilfrid Carré, Valérie Dupé, Christèle Dubourg, Houda Hamdi-Rozé, Marie de Tayrac, Aurélie Rizzo, 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], ANR-12-BSV1-0007-01, Agence Nationale de la Recherche, AMP2016, Agence de la Biomedecine, ANR-12-BSV1-0007,HOLOPRO,Etude des mécanismes moléculaires impliqués dans l'holoprosencéphalie(2012), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Male, Pituitary gland, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, brain development, Chick Embryo, Haploinsufficiency, Biochemistry, SHH, Cohort Studies, Mice, 0302 clinical medicine, Endocrinology, Holoprosencephaly, Pregnancy, Sonic hedgehog, Cells, Cultured, Receptors, Notch, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell biology, NOTCH, medicine.anatomical_structure, embryonic structures, Female, Signal Transduction, medicine.medical_specialty, Hypothalamo-Hypophyseal System, animal structures, Notch signaling pathway, Hypothalamus, rare disease, Context (language use), Mice, Transgenic, Biology, 03 medical and health sciences, Downregulation and upregulation, Internal medicine, medicine, Animals, Humans, Hedgehog Proteins, Retrospective Studies, Biochemistry (medical), medicine.disease, Embryo, Mammalian, Disease Models, Animal, 030104 developmental biology, Forebrain, biology.protein, 030217 neurology & neurosurgery
Abstract: Context In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown. Objective The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain. Design In this study, we have used a chemical inhibition approach in the chick model and a genetic approach in the mouse model. We also reported results obtained from the clinical diagnosis of a cohort composed of 141 holoprosencephaly patients. Results We demonstrated that inhibition of NOTCH signaling in chick embryos as well as in mouse embryos induced a specific downregulation of SHH in the anterior hypothalamus. Our data in the mouse also revealed that the pituitary gland was the most sensitive tissue to Shh insufficiency and that haploinsufficiency of the SHH and NOTCH signaling pathways synergized to produce a malformed pituitary gland. Analysis of a large holoprosencephaly cohort revealed that some patients possessed multiple heterozygous mutations in several regulators of both pathways. Conclusions These results provided new insights into molecular mechanisms underlying the extreme phenotypic variability observed in human holoprosencephaly. They showed how haploinsufficiency of the SHH and NOTCH activity could contribute to specific congenital hypopituitarism that was associated with a sella turcica defect.
Published: 2020

29. Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein

Author: Luis Aníbal Diambra, Valérie Dupé, Monika Ferovova, Marie de Tayrac, Erwan Watrin, Véronique David, Christèle Dubourg, Sylvie Odent, Artem Kim, Farah Diab, Jerome Le Douce, 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 Pontchaillou [Rennes], Universidad Nacional de la Plata [Argentine] (UNLP), ANR-12-BSV1-0007-01, Agence Nationale de la Recherche, AMP2016, Agence de la Biomédecine, PRTK 2016, Institut National Du Cancer, FDT201904008099, Fondation pour la Recherche Médicale, PMO1201204, Fondation Maladie Rares, Fondation Recherche Medicale, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and ANR-12-BSV1-0007,HOLOPRO,Etude des mécanismes moléculaires impliqués dans l'holoprosencéphalie(2012)
Subjects: 0301 basic medicine, In silico, Biología, [SDV]Life Sciences [q-bio], brain development, Polymorphism, Single Nucleotide, synonymous variants, 03 medical and health sciences, 0302 clinical medicine, Holoprosencephaly, medicine, Sonic Hedgehog Protein, Humans, Hedgehog Proteins, genetics, Sonic hedgehog, Gene, Genetics, Messenger RNA, biology, codon usage, medicine.disease, clinical practice, 030104 developmental biology, Codon usage bias, Protein Biosynthesis, RNA splicing, biology.protein, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Synonymous single nucleotide variants (sSNVs) have been implicated in various genetic disorders through alterations of pre-mRNA splicing, mRNA structure and miRNA regulation. However, their impact on synonymous codon usage and protein translation remains to be elucidated in clinical context. Here, we explore the functional impact of sSNVs in the Sonic Hedgehog (SHH) gene, identified in patients affected by holoprosencephaly, a congenital brain defect resulting from incomplete forebrain cleavage. We identified eight sSNVs in SHH, selectively enriched in holoprosencephaly patients as compared to healthy individuals, and systematically assessed their effect at both transcriptional and translational levels using a series of in silico and in vitro approaches. Although no evidence of impact of these sSNVs on splicing, mRNA structure or miRNA regulation was found, five sSNVs introduced significant changes in codon usage and were predicted to impact protein translation. Cell assays demonstrated that these five sSNVs are associated with a significantly reduced amount of the resulting protein, ranging from 5% to 23%. Inhibition of the proteasome rescued the protein levels for four out of five sSNVs, confirming their impact on protein stability and folding. Remarkably, we found a significant correlation between experimental values of protein reduction and computational measures of codon usage, indicating the relevance of in silico models in predicting the impact of sSNVs on translation. Considering the critical role of SHH in brain development, our findings highlight the clinical relevance of sSNVs in holoprosencephaly and underline the importance of investigating their impact on translation in human pathologies., Centro Regional de Estudios Genómicos
Published: 2020

30. Prenatal phenotype of 22q11 micro-duplications: A systematic review and report on 12 new cases

Author: Laura Mary, Alinoë Lavillaureix, Adélie Perrot, Philippe Loget, Erika Launay, Anne-Sophie Leborgne, Florence Demurger, Mélanie Fradin, Gwenaelle Le Bouar, Chloé Quélin, Christèle Dubourg, Laurent Pasquier, Sylvie Odent, Marc-Antoine Belaud-Rotureau, Sylvie Jaillard, Chard-Hutchinson, Xavier, École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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 Pontchaillou [Rennes], Clinique mutualiste La Sagesse, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Centre Hospitalier Universitaire [Rennes], and This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Subjects: Male, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 22, [SDV]Life Sciences [q-bio], Infant, Newborn, [SDV.GEN] Life Sciences [q-bio]/Genetics, General Medicine, Genotype-phenotype, Phosphoproteins, 22q11, [SDV] Life Sciences [q-bio], Fetus, Phenotype, aCGH, Chromosome Duplication, DiGeorge Syndrome, Genetics, Humans, Prenatal, Abnormalities, Multiple, Female, Foetal, Genetics (clinical), Adaptor Proteins, Signal Transducing
Abstract: International audience; The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.
Published: 2022

31. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author: Benjamin Cogné, Stephen Sanders, François Rivier, Tahir N. Khan, Mireille Claustres, Gaetan Lesca, Lihadh Al-Gazali, Annick Vogels, Sarah Weckhuysen, Nicholas Katsanis, Stéphane Bézieau, Thomas Besnard, Maxime Cadieux-Dion, Julitta de Bellescize, Katrin Õunap, Anne Boland, Aurora Pujol, Monica H. Wojcik, Maria J. Guillen Sacoto, Paul Rollier, Laurent Pasquier, Bertrand Isidor, Sébastien Küry, Hilde Van Esch, Aisha Al Shamsi, Megan T. Cho, Kyle Retterer, Michel Koenig, Christèle Dubourg, Andreas G. Chiocchetti, Damien Sanlaville, Erica E. Davis, Claire Guissart, Sander Pajusalu, Hannah Stamberger, Xenia Latypova, Shannon Sattler, Souphatta Sasorith, Isabelle Thiffault, Marie Vincent, Nicolas Leboucq, Irman Forghani, Lynn Schema, Sylvie Odent, Marie T. McDonald, Lauren E. Grote, Susanne Kjaergaard, Wilfrid Carré, Rena Pressman, Emily G. Farrow, Jean-François Deleuze, Carol J Saunders, Deborah Barbouth, Danielle Karlowicz, Nicole P. Safina, Kirsty McWalter, Christine M. Freitag, Wim Van Paesschen, Rebecca Willaert, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universitätsklinikum Leipzig, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Human Molecular Genetics, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de biologie moléculaire, Hôpital Pontchaillou, Centre National de Genotypage, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Pediatrics, Faculty of Medicine and Health Sciences, UAE University, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de Neuroradiologie[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de Génétique, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Center for Human Disease Modeling, Duke University [Durham], Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service de génétique clinique, hôpital Sud, National Human Genome Research Institute, UM1 HG008900, National Eye Institute, PUT355, Eesti Teadusagentuur, 2011-RARE-004-01, Agence Nationale pour la Recherche/E-rare Joint-Transnational-Call 2011, National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program, R01 MH106826, NIH, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), and Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud
Subjects: Male, 0301 basic medicine, Autism, [SDV]Life Sciences [q-bio], Neurodegenerative, Medical and Health Sciences, RORA, Purkinje Cells, 0302 clinical medicine, Neurodevelopmental disorder, Group F, 80 and over, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, Zebrafish, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genes, Dominant, Pediatric, Genetics & Heredity, Aged, 80 and over, Genetics, Malalties neurodegeneratives, Brain, Nuclear Receptor Subfamily 1, Group F, Member 1, Neurodegenerative Diseases, Syndrome, Biological Sciences, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Mental Health, intellectual disability, Child, Preschool, Larva, Neurological, Female, Cerebellar atrophy, medicine.symptom, Haploinsufficiency, Adult, Member 1, Ataxia, Cerebellar Ataxia, Nuclear Receptor Subfamily 1, Adolescent, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Biology, Article, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, Dominant, Autistic Disorder, Allele, Preschool, Alleles, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, Animal, Point mutation, Genetic Complementation Test, Neurosciences, medicine.disease, neurodevelopmental disorder, Brain Disorders, Disease Models, Animal, 030104 developmental biology, Genes, autistic features, Disease Models, Mutation, epilepsy, Human medicine, cerebellar ataxia, Missense, Autisme, dual molecular effects, 030217 neurology & neurosurgery
Abstract: RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome. ispartof: American Journal of Human Genetics vol:102 issue:5 pages:744-759 ispartof: location:United States status: published
Published: 2018

32. Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author: Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, and Ping Yee Billie Au
Subjects: Genetics (clinical)
Published: 2021

33. IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients

Author: Darina Prchalova, Philippe Pm Campeau, Bénédicte Duban-Bedu, Jacques L. Michaud, Marije Koopmans, Arnold Munnich, Christel Depienne, Marilyn Tallot, Fadi F. Hamdan, Eveline Hagebeuk, Marie-Laure Moutard, Anna Kaminska, Petra Laššuthová, Kathryn G. Miller, Ange Line Bruel, Xilma Xr Ortiz-Gonzalez, Shoji Ichikawa, Ingo Helbig, Ethan Em Goldberg, Sarah Weckhuysen, Daphné Lehalle, Elena Gardella, Marie-Bertille Dehouck, Claude Besmond, Patrick Edery, Christine Ioos, Pauline Marzin, Christine Coubes, Julien Buratti, Rima Nabbout, Hubert Journel, Audrey Putoux, Giulia Barcia, Laurence Hubert, Claire Davidson, Berten Ceulemans, Ana Ag Cristancho, Fiona Cunningham, Chloé Quélin, Christèle Dubourg, Aoife Ac McMahon, Thomas Smol, Delphine Héron, Katalin Štěrbová, Katherine Kl Helbig, Boris Keren, Ivan Shelihan, Damien Lederer, Rikke Rs Møller, Emílie Vyhnálková, Alyssa R. Rosen, Natasha Shur, Julie Gauthier, Dragan Marjanovic, Berge Ba Minassian, Marleen Simon, Ledia Brunga, Guillaume Smits, Sandra Janssens, Catheline Vilain, Gaetan Lesca, Caroline Nava, Jasper J. van der Smagt, Laurent Villard, Cyril Mignot, Samuel P. Yang, Joelle Roume, Julie Soblet, JM Pinard, Stéphanie Gobin-Limballe, Bobby P. C. Koeleman, Miroslava Hancarova, Elizabeth J. Donner, Nienke Ne Verbeek, Marie-Line Jacquemont, Marjan J. A. van Kempen, Julia Metreau, David Geneviève, Joannella Morales, Peter M. van Hasselt, Christine Barnerias, Caroline Lacoste, Claire Bar, Thierry Bienvenu, Mathieu Milh, Elsa Rossignol, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), CHU Sainte Justine [Montréal], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Hospices Civils de Lyon (HCL), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de neurologie pédiatrique [CHU Necker], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hôpital Cochin [AP-HP], Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, The Hospital for sick children [Toronto] (SickKids), University of Antwerp (UA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Children’s Hospital of Philadelphia (CHOP ), Hôpital Saint-Vincent de Paul, 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 ), University of Southern Denmark (SDU), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University Hospital Motol [Prague], Hôpital Raymond Poincaré [AP-HP], Center for Medical Genetics [Ghent], Ghent University Hospital, University Medical Center [Utrecht], Institut de Pathologie et Génétique [Gosselies] (I.P.G.), 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, CHI Créteil, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Trousseau [APHP], Université de Lyon, CHI Poissy-Saint-Germain, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université libre de Bruxelles (ULB), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Antwerp University Hospital [Edegem] (UZA), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Rennes], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en neurosciences de Lyon (CRNL), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), 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 Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Centre de Psychiatrie et Neurosciences (U894)
Subjects: 0301 basic medicine, Male, Génétique clinique, [SDV]Life Sciences [q-bio], Medizin, Physiology, 030105 genetics & heredity, Seizures/epidemiology, Epilepsy, Brain Diseases/epidemiology, X-linked inheritance, Intellectual disability, Guanine Nucleotide Exchange Factors, Protein Isoforms, Missense mutation, Genetics(clinical), 10. No inequality, Non-U.S. Gov't, Genetics (clinical), X-linked recessive inheritance, ComputingMilieux_MISCELLANEOUS, Brain Diseases, Sex Characteristics, Research Support, Non-U.S. Gov't, Brain, Sciences bio-médicales et agricoles, 3. Good health, Pedigree, Phenotype, intellectual disability, Female, Brain/growth & development, Sex characteristics, Génétique moléculaire, Guanine Nucleotide Exchange Factors/genetics, Encephalopathy, Research Support, X-inactivation, Article, 03 medical and health sciences, Seizures, Protein Isoforms/genetics, medicine, Journal Article, IQSEC2, Humans, Intellectual Disability/epidemiology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Infant, Newborn, isoforms, Correction, Infant, medicine.disease, Newborn, Human genetics, 030104 developmental biology, Mutation, epilepsy, Human medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

34. Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Author: Meron Azage, David B. Everman, Brooke T. Smith, Steffen Syrbe, Stephen W. Scherer, Jennifer Keller-Ramey, Gregory M. Cooper, Verónica Martínez-Cerdeño, Susan M. Hiatt, Mathew J Wallis, Dmitriy Niyazov, Benjamin Büttner, Rami Abou Jamra, Ryan K. C. Yuen, Johannes R. Lemke, Natasha J Brown, Amber Begtrup, Richard E. Person, Barbara Kellam, Chloé Quélin, Heinrich Sticht, Laurence J. Walsh, Angelo Harlan De Crescenzo, Konstantinos Zarbalis, Jonathan B. Strober, Susan Walker, Alexios A Panoutsopoulos, Shuxi Liu, Diana Le Duc, Urania Kotzaeridou, Michael S. Hildebrand, Michael C. Pride, Eleonora Napoli, Jacqueline N. Crawley, Francis Jeshira Reynoso Santos, Katelyn Payne, Renee Bend, Sandra Yang, Megan T. Cho, Evdokia Anagnostou, Cecilia R Giulivi, Rhonda E. Schnur, Lori Orosco, Andreas Ziegler, Jan H Doering, Christèle Dubourg, Jill L. Silverman, Universität Leipzig [Leipzig], University of California [Davis] (UC Davis), University of California, GeneDx [Gaithersburg, MD, USA], 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), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Shriners Hospitals for Children, U54 HD079125, National Institute of Child Health and Human Development, R21MH115347, National Institute of Mental Health, 286567, Simons Foundation, Nancy Lurie Marks Family Foundation, UM1HG007301, National Human Genome Research Institute, Clinician Scientist Programm, Medizinische Fakultät der Universität Leipzig, Shriners Hospitals for Children Postdoctoral Fellowship, The MIND Institute IDDRC, Universität Leipzig, University of California (UC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud
Subjects: 0301 basic medicine, Proband, Male, Microcephaly, Secondary, [SDV]Life Sciences [q-bio], Autophagy-Related Proteins, Medical and Health Sciences, Transgenic, Mice, 0302 clinical medicine, Intellectual disability, 2.1 Biological and endogenous factors, Aetiology, Child, Exome, ComputingMilieux_MISCELLANEOUS, Pediatric, Brain, Adaptor Proteins, Organ Size, Mental Health, WDFY3, Autism spectrum disorder, intellectual disability, brain size, Neurological, Female, medicine.symptom, Haploinsufficiency, Biotechnology, Protein Structure, Adolescent, Intellectual and Developmental Disabilities (IDD), Biology, neurodevelopmental delay, 03 medical and health sciences, Clinical Research, medicine, Genetics, Animals, Humans, Preschool, Neurology & Neurosurgery, Psychology and Cognitive Sciences, Macrocephaly, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, Stem Cell Research, Associative learning, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery
Abstract: The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.
Published: 2019

35. Correction: IQSEC2-related encephalopathy in males and females:a comparative study including 37 novel patients

Author: Petra Laššuthová, Kathryn G. Miller, Jacques L. Michaud, Sarah Weckhuysen, Claude Besmond, Stéphanie Gobin-Limballe, Emílie Vyhnálková, Aoife McMahon, Peter M. van Hasselt, Christine Barnerias, Laurence Hubert, Joannella Morales, Daphné Lehalle, Caroline Lacoste, Rima Nabbout, Hubert Journel, Jasper J. van der Smagt, Patrick Edery, Marjan J. A. van Kempen, Samuel P. Yang, Fiona Cunningham, Thomas Smol, Delphine Héron, Darina Prchalova, David Geneviève, Thierry Bienvenu, Mathieu Milh, Bénédicte Duban-Bedu, Ledia Brunga, Marleen Simon, Ana G. Cristancho, Ethan M. Goldberg, Sandra Janssens, Christel Depienne, Miroslava Hancarova, Shoji Ichikawa, Berge A. Minassian, Ivan Shelihan, Elsa Rossignol, Ange Line Bruel, Elena Gardella, Marije Koopmans, Arnold Munnich, Natasha Shur, Pauline Marzin, Ingo Helbig, Julien Buratti, Alyssa R. Rosen, Giulia Barcia, Claire Davidson, Berten Ceulemans, Marilyn Tallot, Marie Line Jacquemont, Guillaume Smits, Catheline Vilain, Katherine L. Helbig, Gaetan Lesca, Rikke S. Møller, Claire Bar, Marie Laure Moutard, Caroline Nava, Marie Bertille Dehouck, Julie Soblet, Philippe M. Campeau, Cyril Mignot, Laurent Villard, Joelle Roume, Julia Metreau, Dragan Marjanovic, Damien Lederer, Audrey Putoux, Chloé Quélin, Fadi F. Hamdan, Boris Keren, Anna Kaminska, Xilma R. Ortiz-Gonzalez, Christine Ioos, Christine Coubes, Julie Gauthier, Nienke E. Verbeek, Bobby P. C. Koeleman, Eveline Hagebeuk, Jean Marc Pinard, Katalin Štěrbová, Christèle Dubourg, and Elizabeth J. Donner
Subjects: Pediatrics, medicine.medical_specialty, Text mining, business.industry, Published Erratum, Encephalopathy, Medizin, MEDLINE, Medicine, business, medicine.disease, Genetics (clinical)
Abstract: This Article was originally published under Nature Research’s License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
Published: 2019

36. Author Correction: A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author: Stephan Kemeny, Sandrine Passemard, Sandra Chantot-Bastaraud, Chloé Quélin, Laurence Perrin, Julien Buratti, Patrick Edery, Céline Dupont, Chantal Missirian, Philippe Vago, Alexandra Afenjar, Marie-Laure Vuillaume, Yline Capri, Klaus Dieterich, Laila El Khattabi, Charles Coutton, Françoise Devillard, Annick Toutain, Alain Verloes, Nicole Philip, Hubert Journel, Véronique Satre, Marie Ducloy, Delphine Héron, Richard Delorme, Cédric Le Caignec, Anne-Claude Tabet, Damien Sanlaville, Isabelle Marey, Laurence Faivre, Christèle Dubourg, Anne-Laure Mosca-Boidron, Laetitia Gouas, Abdelamdjid Benmansour, Jean Chiesa, Séverine Drunat, Cyril Mignot, Aurélia Jacquette, Boris Keren, Claire S. Leblond, Claire Beneteau, Brigitte Benzacken, Vincent Gatinois, Olivier Pichon, Damien Haye, Roberto Toro, Sandra Whalen, Dominique Martin, Thomas Rolland, Thomas Bourgeron, Albert David, Alexandre Mathieu, Mélanie Fradin, Frédérique Amsellem, Bertrand Isidor, James Lespinasse, Caroline Rooryck, Jacques Puechberty, Eva Pipiras, Lucile Pinson, Didier Lacombe, Jonathan M. Levy, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], CHU Trousseau [APHP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), CHU de Lyon, Centre Hospitalier Universitaire [Grenoble] (CHU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier de Chambéry (C.H.de Chambéry), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Le Mans (CH Le Mans), AP-HP Hôpital universitaire Robert-Debré [Paris], Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, UF de Cytogénétique, Institut Pasteur [Paris], Université de Bordeaux (UB), École normale supérieure - Rennes (ENS Rennes), Unité de Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Laboratoire Interdisciplinaire Carnot de Bourgogne (LICB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de génétique clinique [Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Service de Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Gatonero SA, Hôtel-Dieu de Nantes, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale, CHU Clermont-Ferrand-Hôpital d'Estaing, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des anomalies du développement [Lyon], UF de Biochimie et Génétique Moléculaire (BGM), CHU Grenoble, Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), IMAXIO, Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire Carémeau [Nîmes], Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Bretagne Atlantique [Vannes], Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), and Rolland, Thomas
Subjects: medicine.medical_specialty, lcsh:QH426-470, lcsh:Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, 0302 clinical medicine, Phelan-McDermid syndrome, Genetics, medicine, 0501 psychology and cognitive sciences, In patient, Clinical genetics, Author Correction, Psychiatry, Molecular Biology, Genetics (clinical), business.industry, lcsh:R, Neurodevelopmental disorders, 05 social sciences, lcsh:Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, business, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract: Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders., The underlying genetics of Phelan-McDermid syndrome Multiple chromosomal changes may impact the severity of symptoms in people with Phelan-McDermid syndrome (PMS). Thomas Bourgeron of the Institut Pasteur and colleagues in France conducted genomic analyses and explored the clinical features of 85 people with PMS, a condition caused by a deletion in the long arm of chromosome 22. It is often associated with severe symptoms such as intellectual disability, autism, and seizures. The chromosomal changes in 65% of those studied were not inherited. MRI brain scans showed visible abnormalities in 23 of 35 patients imaged. The size of the chromosomal deletion varied. Patients with small deletions were more likely to have autistic symptoms while those with large deletions were more likely to be unable to talk. The team also identified genes in chromosome 22 and in other regions of the genome that could modify the severity of PMS symptoms.
Published: 2019

37. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), 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 ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], 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), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019

38. Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility

Author: Ingrid M. Knarston, Marion Beaumont, Célia Ravel, Linda Akloul, Sylvie Jaillard, Christèle Dubourg, Elena J. Tucker, Marc-Antoine Belaud-Rotureau, Andrew H. Sinclair, Katie L. Ayers, Jocelyn van den Bergen, Sylvie Odent, Gorjana Robevska, Céline Pimentel, Guilhem Jouve, Rajini Sreenivasan, Solène Duros, Sonia Grover, Brittany Croft, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Murdoch Children's Research Institute (MCRI), University of Melbourne, Chung Hua University, CHUNational Health and Medical Research Council, NHMRC, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and CCSD, Accord Elsevier
Subjects: Infertility, Steroidogenic factor 1, Adult, endocrine system, endocrine system diseases, [SDV]Life Sciences [q-bio], NR5A1, Menopause, Premature, Physiology, Black People, Premature ovarian insufficiency, Primary Ovarian Insufficiency, Steroidogenic Factor 1, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Ovarian reserve, Ovarian Reserve, Alleles, 030304 developmental biology, Unexplained infertility, 0303 health sciences, 030219 obstetrics & reproductive medicine, business.industry, Female infertility, Obstetrics and Gynecology, medicine.disease, female genital diseases and pregnancy complications, [SDV] Life Sciences [q-bio], Menopause, Diminished ovarian reserve, HEK293 Cells, Gene Expression Regulation, Whole-exome sequencing, Mutation, Female, Ovarian cancer, business, Infertility, Female
Abstract: International audience; Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26–8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance. © 2019 Elsevier B.V.
Published: 2019

39. 11q24.2q24.3 microdeletion in two families presenting features of Jacobsen syndrome, without intellectual disability Role of FLI1, ETS1, and SENCR long noncoding RNA

Author: Solène Conrad, Antoinette Perlat, Kamran Moradkhani, Caroline Thomas, Christèle Dubourg, Sylvie Jaillard, Cécile Pascal, Florence Demurger, Sophie Bayart, Olivier Pichon, Cédric Le Caignec, Mathilde Nizon, Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Hôpital privé du Confluent [Nantes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale [CHU Nantes], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: 0301 basic medicine, Male, Candidate gene, ETS1, [SDV]Life Sciences [q-bio], ARHGAP32, 11q24 deletion, 030105 genetics & heredity, Jacobsen syndrome, Proto-Oncogene Protein c-ets-1, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Jacobsen Distal 11q Deletion Syndrome, 10. No inequality, Gene, Genetics (clinical), Genetic Association Studies, In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, [SDV.GEN]Life Sciences [q-bio]/Genetics, SENCR, business.industry, Proto-Oncogene Protein c-fli-1, FLI1, Facies, medicine.disease, Penetrance, 3. Good health, Pedigree, 030104 developmental biology, Phenotype, Autism spectrum disorder, Karyotyping, Female, RNA, Long Noncoding, business, Haploinsufficiency
Abstract: International audience; This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients.
Published: 2019

40. Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

Author: Linda Akloul, Véronique David, Clarisse Baumann, Sylvie Odent, Laurent Pasquier, Christèle Dubourg, Houda Hamdi-Rozé, Daniel Amram, Charlotte Mouden, Pierre Sarda, Sophie Naudion, Amélie Poidvin, Marie Gonzales, Nicolas Chassaing, Valérie Dupé, Fabienne Prieur, Joelle Roume, Marie de Tayrac, Benmansour Abdelmajid, Annie Levy-Mozziconacci, Christine Coubes, Wilfrid Carré, Annick Toutain, Laurence Faivre-Olivier, Emmanuelle Ginglinger, and Sally-Ann Lynch
Subjects: musculoskeletal diseases, 0301 basic medicine, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Fibroblast growth factor receptor 1, Genetic counseling, Biology, Quantitative trait locus, Bioinformatics, ZIC2, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, FGF8, Holoprosencephaly, GLI2, medicine, Gene, Genetics (clinical)
Abstract: Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.
Published: 2016

41. Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing

Author: Chloé Quélin, Linda Akloul, Véronique David, Christèle Dubourg, Sylvie Odent, Charlotte Mouden, Houda Hamdi-Rozé, H Salhi, G Viot, Valérie Dupé, Wilfrid Carré, Sophie Rose, and P Darnault
Subjects: musculoskeletal diseases, 0301 basic medicine, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Genetic counseling, Biology, Bioinformatics, medicine.disease, Compound heterozygosity, Digenic inheritance, 03 medical and health sciences, 030104 developmental biology, Holoprosencephaly, medicine, Inheritance Patterns, Gene, Exome, Genetics (clinical), Exome sequencing
Abstract: Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year-old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling.
Published: 2016

42. Du cyclope à la réalité

Author: Marie de Tayrac, Christèle Dubourg, Véronique David, and Valérie Dupé
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, General Medicine, 030105 genetics & heredity, Biology, Humanities, General Biochemistry, Genetics and Molecular Biology
Published: 2017

43. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author: Shoji Ichikawa, Ilaria Rivolta, Anna Binda, Laurie S. Sadler, Sonia Figueiroa, Renzo Guerrini, Annick Laridon, Pasquale Striano, Katalin Sterbova, Bina Santoro, Petra Laššuthová, Maria Margherita Mancardi, Francesca Ragona, Anna Rosati, Fernando Kok, Laura Canafoglia, Daniele Frattini, Elena Freri, Christine Coubes, Davide Mei, Bobby P. C. Koeleman, Daniel Bauer, Carla Marini, Christel Depienne, Carlotta Spagnoli, Sophie Scheidecker, Carlo Fusco, Tiziana Granata, Barbara Castellotti, Eva H. Brilstra, Federico Melani, Cristina Garrido, Cinzia Gellera, A. Micheil Innes, Wilfrid Carré, Christèle Dubourg, Elena Parrini, Alessandro Porro, Caroline Nava, Maria Giardino, Sophie Julia, Manuela Santos, Yves Alembik, Eric LeGuern, Andrea Barbuti, Silvana Franceschetti, Federico Zara, Paul Kuentz, Raffaella Milanesi, Catherine Mercer, Carine Dalle, Julien Thevenon, Nicolas Deconinck, Agnès Rastetter, Laurent Pasquier, Kay Hamacher, Renske Oegema, Gerhard Thiel, Dario DiFrancesco, Tiziana Pisano, Chelsea Chambers, Jacopo C. DiFrancesco, Guillaume Smits, Katherine L. Helbig, Julie Soblet, Jana Neupauerová, Damien R Clark, Johannes R. Lemke, Radhika Dhamija, Anna Moroni, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Pontchaillou [Rennes], Les Hôpitaux Universitaires de Strasbourg (HUS), Children’s Hospital of Philadelphia (CHOP ), University Hospital Motol [Prague], University of Genoa (UNIGE), Université libre de Bruxelles (ULB), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), 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), Université de Strasbourg (UNISTRA), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Marini, C, Porro, A, Rastetter, A, Dalle, C, Rivolta, I, Bauer, D, Oegema, R, Nava, C, Parrini, E, Mei, D, Mercer, C, Dhamija, R, Chambers, C, Coubes, C, Thévenon, J, Kuentz, P, Julia, S, Pasquier, L, Dubourg, C, Carré, W, Rosati, A, Melani, F, Pisano, T, Giardino, M, Innes, A, Alembik, Y, Scheidecker, S, Santos, M, Figueiroa, S, Garrido, C, Fusco, C, Frattini, D, Spagnoli, C, Binda, A, Granata, T, Ragona, F, Freri, E, Franceschetti, S, Canafoglia, L, Castellotti, B, Gellera, C, Milanesi, R, Mancardi, M, Clark, D, Kok, F, Helbig, K, Ichikawa, S, Sadler, L, Neupauerová, J, Laššuthova, P, Šterbová, K, Laridon, A, Brilstra, E, Koeleman, B, Lemke, J, Zara, F, Striano, P, Soblet, J, Smits, G, Deconinck, N, Barbuti, A, Difrancesco, D, Leguern, E, Guerrini, R, Santoro, B, Hamacher, K, Thiel, G, Moroni, A, Di Francesco, J, and Depienne, C
Subjects: 0301 basic medicine, Proband, Male, Models, Molecular, Potassium Channels, [SDV]Life Sciences [q-bio], Medizin, medicine.disease_cause, Epileptogenesis, Membrane Potentials, Epilepsy, 0302 clinical medicine, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Missense mutation, Child, Genetics, Mutation, Middle Aged, Phenotype, 3. Good health, Transmembrane domain, clinical spectrum, epilepsy, HCN1, intellectual disability, ion channel, Child, Preschool, Epilepsy, Generalized, Female, Spasms, Infantile, Adult, Adolescent, CHO Cells, Biology, 03 medical and health sciences, Young Adult, Cricetulus, medicine, Animals, Humans, Generalized epilepsy, Genetic Association Studies, Aged, Infant, medicine.disease, Electric Stimulation, 030104 developmental biology, Mutagenesis, Site-Directed, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: International audience; Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.
Published: 2018

44. Targeted panel sequencing establishes the implication of planar cell polarity pathway and involves new candidate genes in neural tube defect disorders

Author: Hubert Journel, Sylvie Odent, Valérie Dupé, Erwan Watrin, Mélanie Fradin, Linda Akloul, Laurent Pasquier, Chloé Quélin, Wilfrid Carré, Christèle Dubourg, Véronique David, Marie Beaumont, Houda Hamdi-Rozé, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), CHU Pontchaillou, CORECT, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, Candidate gene, Sequence analysis, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Computational biology, Biology, Cohort Studies, 03 medical and health sciences, Mice, Pregnancy, Genetics, medicine, Animals, Humans, Neural Tube Defects, Child, Gene, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Neural tube defect, 030305 genetics & heredity, Embryogenesis, Neural tube, Cell Polarity, Sequence Analysis, DNA, medicine.disease, Hedgehog signaling pathway, Human genetics, Disease Models, Animal, medicine.anatomical_structure, Female, Transcriptome, Signal Transduction
Abstract: International audience; Neural tube defect disorders are developmental diseases that originate from an incomplete closure of the neural tube during embryogenesis. Despite high prevalence-1 out of 3000 live births-their etiology is not yet established and both environmental and genetic factors have been proposed, with a heritability rate of about 60%. Studies in mouse models as well as in human have further suggested a multifactorial pattern of inheritance for neural tube defect disorders. Here, we report results obtained from clinical diagnosis and NGS analysis of a cohort composed of 52 patients. Using a candidate gene panel approach, we identified variants in known genes of planar cell polarity (PCP) pathway, although with higher prevalence than previously reported. Our study also reveals variants in novel genes such as FREM2 and DISP1. Altogether, these results confirm the implication of the PCP genes and involve the FRAS/FREM2 complex and Sonic Hedgehog signaling as novel components in the appearance of NTDs.
Published: 2018

45. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

Author: Sophie Scheidecker, Françoise Devillard, Gaetan Lesca, Maryline Carneiro, Christèle Dubourg, Ganaëlle Remerand, Catherine Badens, Odile Boespflug-Tanguy, Nathalie Marle, Serge Romana, Nadia Bahi-Buisson, Jean-Paul Bonnefont, Hubert Journel, Bénédicte Duban-Bedu, Brigitte Gilbert-Dussardier, Mathilde Nizon, Nathalie Perreton, Sophie Julia, Cyril Goizet, Delphine Héron, Véronique Satre, Marguerite Miguet, Joris Andrieux, Pierre-Simon Jouk, Laurence Perrin, Renaud Touraine, Ghislaine Plessis, Dominique Martin-Coignard, Caroline Rooryck, Catherine Vincent-Delorme, Laurence Faivre, Salima El Chehadeh, Thierry Bienvenu, Jean-Luc Alessandri, Anne-Claude Tabet, Laurent Pasquier, Martine Raynaud, Réseau AChro-Puce, Marjolaine Willems, Bruno Leheup, Marianne Till, Jeanne Amiel, Jacqueline Vigneron, Nicole Philip, Valérie Kremer, Massimiliano Rossi, Boris Keren, Annick Toutain, Fabienne Prieur, Bertrand Isidor, Séverine Drunat, Marilyn Lackmy-Port-Lis, Albert David, Christel Thauvin-Robinet, Damien Sanlaville, Laetitia Lambert, Lydie Burglen, Klaus Dieterich, Catherine Sarret, Anne Moncla, Didier Lacombe, Fanny Laffargue, Kim Maincent, Marlène Rio, Clarisse Baumann, Mathilde Lefebvre, Sabine Sigaudy, Laurent Guibaud, Adeline Vigouroux, Valérie Malan, Patrick Callier, Chantal Missirian, Christophe Philippe, Christine Francannet, Anne-Laure Mosca-Boidron, Valérie Cormier-Daire, Cédric Le Caignec, Vincent des Portes, Charles Coutton, Alexandra Afenjar, Sandrine Chantot-Bastaraud, Julien Thevenon, Mylène Béri-Dexheimer, Hilde Van Esch, Bernard Echenne, Jean-Marie Cuisset, Jean-Michel Pedespan, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Clinique (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Image Guided Clinical Neurosciences and Connectomics (IGCNC), Université d'Auvergne - Clermont-Ferrand I (UdA), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Génétique Médicale (CHU de Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neuro-pédiatrie (CHRU de Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Médicale, Hopital Jeanne de Flandre, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Radiologie [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de génétique clinique [CHU Necker], Département de neurologie pédiatrique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), 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), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service de génétique clinique [Debré], Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, Institut National de la Santé et de la Recherche Médicale (INSERM)-École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux, Service de Génétique Médicale du CHU de Bordeaux, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biologie Moléculaire (MARSEILLE - Biolo Moléculaire), Assistance Publique - Hôpitaux de Marseille (APHM), CIC 1407, Hospices Civils de Lyon (HCL), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], GHICL-Hôpital Saint Vincent de Paul, Service de Neuropédiatrie [CHU Necker - Enfants Malades], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Moléculaire [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Service de Neurologie Pédiatrique [CHU Lyon], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre for Human Genetics, University Hospitals Leuven [Leuven], Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de référence des déficiences intellectuelles de causes rares (Hospices Civils de Lyon), Hospices civils de Lyon (HCL), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Groupement Hospitalier Lyon-Est (GHE), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, MECP2 duplication syndrome, MECP2gene, Scoliosis, MECP2duplication syndrome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, Genetics, medicine, Spasticity, Genetics (clinical), X-linked, Vasomotor, business.industry, facial dysmorphism, medicine.disease, Gait, Hypotonia, 3. Good health, 030104 developmental biology, Xq28 duplication, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine.symptom, business, 030217 neurology & neurosurgery, genetic counselling
Abstract: The Xq28 duplication involving theMECP2gene (MECP2duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitialMECP2duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype ofMECP2duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
Published: 2018

46. Recent advances in understanding inheritance of holoprosencephaly

Author: Sylvie Odent, Véronique David, Valérie Dupé, Artem Kim, Erwan Watrin, Marie de Tayrac, Christèle Dubourg, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], 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), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, Male, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, complex disorder, Genetic counseling, Inheritance Patterns, Genes, Recessive, Genetic Counseling, Biology, 03 medical and health sciences, Holoprosencephaly, Pregnancy, Prenatal Diagnosis, Genetics, medicine, Humans, Hedgehog Proteins, oligogenic inheritance, Genetic Testing, Genetics (clinical), Chromosome Aberrations, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, Inheritance (genetic algorithm), Genetic disorder, Autosomal dominant trait, Brain, Sonic hedgehog, Oligogenic Inheritance, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, holoprosencephaly, Evolutionary biology, Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; Holoprosencephaly (HPE) is a complex genetic disorder of the developing forebrain characterized by high phenotypic and genetic heterogeneity. HPE was initially defined as an autosomal dominant disease, but recent research has shown that its mode of transmission is more complex. The past decade has witnessed rapid development of novel genetic technologies and significant progresses in clinical studies of HPE. In this review, we recapitulate genetic epidemiological studies of the largest European HPE cohort and summarize the novel genetic discoveries of HPE based on recently developed diagnostic methods. Our main purpose is to present different inheritance patterns that exist for HPE with a particular emphasis on oligogenic inheritance and its implications in genetic counseling.
Published: 2018

47. Further delineation of the

Author: Marguerite, Miguet, Laurence, Faivre, Jeanne, Amiel, Mathilde, Nizon, Renaud, Touraine, Fabienne, Prieur, Laurent, Pasquier, Mathilde, Lefebvre, Julien, Thevenon, Christèle, Dubourg, Sophie, Julia, Catherine, Sarret, Ganaëlle, Remerand, Christine, Francannet, Fanny, Laffargue, Odile, Boespflug-Tanguy, Albert, David, Bertrand, Isidor, Jacqueline, Vigneron, Bruno, Leheup, Laetitia, Lambert, Christophe, Philippe, Mylène, Béri-Dexheimer, Jean-Marie, Cuisset, Joris, Andrieux, Ghislaine, Plessis, Annick, Toutain, Laurent, Guibaud, Valérie, Cormier-Daire, Marlene, Rio, Jean-Paul, Bonnefont, Bernard, Echenne, Hubert, Journel, Lydie, Burglen, Sandrine, Chantot-Bastaraud, Thierry, Bienvenu, Clarisse, Baumann, Laurence, Perrin, Séverine, Drunat, Pierre-Simon, Jouk, Klaus, Dieterich, Françoise, Devillard, Didier, Lacombe, Nicole, Philip, Sabine, Sigaudy, Anne, Moncla, Chantal, Missirian, Catherine, Badens, Nathalie, Perreton, Christel, Thauvin-Robinet, Réseau, AChro-Puce, Jean-Michel, Pedespan, Caroline, Rooryck, Cyril, Goizet, Catherine, Vincent-Delorme, Bénédicte, Duban-Bedu, Nadia, Bahi-Buisson, Alexandra, Afenjar, Kim, Maincent, Delphine, Héron, Jean-Luc, Alessandri, Dominique, Martin-Coignard, Gaëtan, Lesca, Massimiliano, Rossi, Martine, Raynaud, Patrick, Callier, Anne-Laure, Mosca-Boidron, Nathalie, Marle, Charles, Coutton, Véronique, Satre, Cédric Le, Caignec, Valérie, Malan, Serge, Romana, Boris, Keren, Anne-Claude, Tabet, Valérie, Kremer, Sophie, Scheidecker, Adeline, Vigouroux, Marilyn, Lackmy-Port-Lis, Damien, Sanlaville, Marianne, Till, Maryline, Carneiro, Brigitte, Gilbert-Dussardier, Marjolaine, Willems, Hilde, Van Esch, Vincent Des, Portes, and Salima, El Chehadeh
Subjects: Adult, Male, Chromosomes, Human, X, Epilepsy, Adolescent, Methyl-CpG-Binding Protein 2, Developmental Disabilities, Hypertension, Pulmonary, Infant, Stereotypic Movement Disorder, Pedigree, Young Adult, Hyperopia, Phenotype, Child, Preschool, Intellectual Disability, Mental Retardation, X-Linked, Somatosensory Disorders, Exotropia, Humans, France, Child
Abstract: The Xq28 duplication involving the
Published: 2017

48. A framework to identify modifier genes in patients with Phelan-McDermid syndrome

Author: Séverine Drunat, Frédérique Amsellem, Dominique Martin, Laurence Faivre, Sandra Chantot-Bastaraud, Bertrand Isidor, James Lespinasse, Sandrine Passemard, Jean Chiesa, Roberto Toro, Olivier Pichon, Françoise Devillard, Céline Dupont, Damien Haye, Julien Buratti, Hubert Journel, Sandra Whalen, Marie Ducloy, Cédric Le Caignec, Thomas Rolland, Alexandre Mathieu, Jean-Michel Dupont, Marie-Laure Vuillaume, Annick Toutain, Alain Verloes, Delphine Héron, Didier Lacombe, Jonathan M. Levy, Nicole Philip, Damien Sanlaville, Laurence Perrin, Anne-Claude Tabet, Laetitia Gouas, Caroline Rooryck, Mélanie Fradin, Richard Delorme, Philippe Vago, Christèle Dubourg, Eva Pipiras, Klaus Dieterich, Vincent Gatinois, Claire Beneteau, Jacques Puechberty, Thomas Bourgeron, Véronique Satre, Aurélia Jacquette, Lucile Pinson, Boris Keren, Albert David, Brigitte Benzacken, Anne-Laure Mosca-Boidron, Cyril Mignot, Charles Coutton, Patrick Edery, Chantal Missirian, Chloé Quélin, Alexandra Afenjar, Yline Capri, Stephan Kemeny, Abdelamdjid Benmansour, and Isabelle Marey
Subjects: Genetics, 0303 health sciences, Locus (genetics), Biology, medicine.disease, Corpus callosum, Major gene, SHANK3 Gene, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, medicine, Autism, In patient, 030217 neurology & neurosurgery, 030304 developmental biology, Modifier Genes
Abstract: Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability, speech impairment, and autism spectrum disorders (ASD). It results from a deletion of the 22q13 locus that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors modulating the severity of the syndrome remain largely unknown. In this study, we investigated 85 PMS patients with different 22q13 rearrangements (78 deletions, 7 duplications). We first explored their clinical features and provide evidence for frequent corpus callosum abnormalities. We then mapped candidate genomic regions at the 22q13 locus associated with risk of clinical features, and suggest a second locus associated with absence of speech. Finally, in some cases, we identified additional rearrangements at loci associated with ASD, potentially modulating the severity of the syndrome. We also report the first SHANK3 deletion transmitted to five affected daughters by a mother without intellectual disability nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
Published: 2017

49. A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author: Anne-Claude Tabet, Thomas Rolland, Marie Ducloy, Jonathan Lévy, Julien Buratti, Alexandre Mathieu, Damien Haye, Laurence Perrin, Céline Dupont, Sandrine Passemard, Yline Capri, Alain Verloes, Séverine Drunat, Boris Keren, Cyril Mignot, Isabelle Marey, Aurélia Jacquette, Sandra Whalen, Eva Pipiras, Brigitte Benzacken, Sandra Chantot-Bastaraud, Alexandra Afenjar, Delphine Héron, Cédric Le Caignec, Claire Beneteau, Olivier Pichon, Bertrand Isidor, Albert David, Laila El Khattabi, Stephan Kemeny, Laetitia Gouas, Philippe Vago, Anne-Laure Mosca-Boidron, Laurence Faivre, Chantal Missirian, Nicole Philip, Damien Sanlaville, Patrick Edery, Véronique Satre, Charles Coutton, Françoise Devillard, Klaus Dieterich, Marie-Laure Vuillaume, Caroline Rooryck, Didier Lacombe, Lucile Pinson, Vincent Gatinois, Jacques Puechberty, Jean Chiesa, James Lespinasse, Christèle Dubourg, Chloé Quelin, Mélanie Fradin, Hubert Journel, Annick Toutain, Dominique Martin, Abdelamdjid Benmansour, Claire S. Leblond, Roberto Toro, Frédérique Amsellem, Richard Delorme, Thomas Bourgeron, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Jean Verdier [AP-HP], CHU Trousseau [APHP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Dijon, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Métropole Savoie [Chambéry], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Hôpital Chubert, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Le Mans (CH Le Mans), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), This work was funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, Centre National de la Recherche Scientifique, University Paris Diderot, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the FondaMental Foundation, the GenMed Labex and the BioPsy Labex. The research leading to these results has received funding from the ERA-Net NEURON Cofund Programme under 'Horizon 2020' (SynPathy project), the ANR SynDivAutism, the Human Brain Project, and from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution., We are grateful to the families for participating in this study. We thank Isabelle Cloëz-Tayarani, Ksenia Bagrintseva and Gaël Millot for helpful discussions and careful reading of the manuscript. This study was funded by a French partnership between the Clinical Research Department of the AP-HP Institution and the Institut Pasteur. It was also supported by the PMS French association (Mrs Meunier), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), European Project: 291840,EC:FP7:HEALTH,FP7-ERANET-2011-RTD,ERA-NET NEURON II(2012), European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service de génétique, cytogénétique, embryologie [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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-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)-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), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], CHU de Lyon, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier de Chambéry (C.H.de Chambéry), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Herrada, Anthony, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Santé Mentale et Addictions - Diversité Synaptique dans l'autisme - - SynDivAutism2013 - ANR-13-SAMA-0006 - SAMENTA - VALID, Network of European funding for Neuroscience research - ERA-NET NEURON II - - EC:FP7:HEALTH2012-01-01 - 2015-12-31 - 291840 - VALID, European Autism Interventions - A Multicentre Study for Developing New Medications - EU-AIMS - - EC:FP7:SP1-JTI2012-04-01 - 2017-03-31 - 115300 - VALID, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: lcsh:Genetics, lcsh:QH426-470, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:R, Neurodevelopmental disorders, lcsh:Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Clinical genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Abstract: International audience; Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes theSHANK3gene.SHANK3is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inheritedSHANK3deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
Published: 2017

50. Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions

Author: Anne Dieux, Frédérique Bonnet-Brilhault, M.-P. Beaumont-Epinette, Marion Gérard, Claude Bendavid, Véronique David, Christèle Dubourg, Cyril Mignot, Sophie Julia, Bertrand Isidor, Sylvie Odent, Massimiliano Rossi, Catherine Barthélémy, Annick Toutain, Alain Verloes, Aurélia Jacquette, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Population-Environnement-Développement (LPED), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, business.industry, Retinoic acid induced 1, 030305 genetics & heredity, Nonsense mutation, Locus (genetics), Bioinformatics, Smith–Magenis syndrome, medicine.disease, 3. Good health, Frameshift mutation, 03 medical and health sciences, Exon, Transcriptional regulation, Medicine, Original Article, business, Gene, Genetics (clinical), 030304 developmental biology
Abstract: Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions.
Published: 2014

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