Author: "Salima El-Chehadeh" / Topic: female - Searchworks@Jio Institute Digital Library Search Results

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39 results on '"Salima El-Chehadeh"'

1. Same performance of exome sequencing before and after fetal autopsy for congenital abnormalities: toward a paradigm shift in prenatal diagnosis?

Author: Nicolas Bourgon, Aurore Garde, Ange-Line Bruel, Mathilde Lefebvre, Frederic Tran Mau-Them, Sebastien Moutton, Arthur Sorlin, Sophie Nambot, Julian Delanne, Martin Chevarin, Charlotte Pöe, Julien Thevenon, Daphné Lehalle, Nolween Jean-Marçais, Paul Kuentz, Laetitia Lambert, Salima El Chehadeh, Elise Schaefer, Marjolaine Willems, Fanny Laffargue, Christine Francannet, Mélanie Fradin, Dominique Gaillard, Sophie Blesson, Alice Goldenberg, Yline Capri, Paul Sagot, Thierry Rousseau, Emmanuel Simon, Christine Binquet, Marie-Laure Ascencio, Yannis Duffourd, Christophe Philippe, Laurence Faivre, Antonio Vitobello, and Christel Thauvin-Robinet
Subjects: Fetus, Pregnancy, Prenatal Diagnosis, Exome Sequencing, Genetics, Humans, Abnormalities, Multiple, Exome, Female, Autopsy, Ultrasonography, Prenatal, Genetics (clinical), Congenital Abnormalities
Abstract: Prenatal exome sequencing could be complex because of limited phenotypical data compared to postnatal/portmortem phenotype in fetuses affected by multiple congenital abnormalities (MCA). Here, we investigated limits of prenatal phenotype for ES interpretation thanks to a blindly reanalysis of postmortem ES data using prenatal data only in fetuses affected by MCA and harboring a (likely)pathogenic variant or a variant of unknown significance (VUS). Prenatal ES identified all causative variant previously reported by postmortem ES (22/24 (92%) and 2/24 (8%) using solo-ES and trio-ES respectively). Prenatal ES identified 5 VUS (in four fetuses). Two of them have been previously reported by postmortem ES. Prenatal ES were negative for four fetuses for which a VUS were diagnosed after autopsy. Our study suggests that prenatal phenotype is not a limitation for implementing pES in the prenatal assessment of unsolved MCA to personalize fetal medicine and could influence indication of postmortem examination.
Published: 2022
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2. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author: Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics
Subjects: Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract: Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
Published: 2023
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3. Periodontal (formerly type <scp>VIII</scp> ) <scp>Ehlers–Danlos</scp> syndrome: Description of 13 novel cases and expansion of the clinical phenotype

Author: Dan Lipsker, Marie-Cécile Manière, Jean Muller, Agathe Chammas, Aymeric Courval, Véronique Geoffroy, Elise Schaefer, Salma Adham, Salima El Chehadeh, Clarisse Billon, Sébastien Gaertner, Karelle Bénistan, Corinne Stoetzel, Agnès Bloch-Zupan, Anne-Claire Bursztejn, Anthony Reyre, Laurence Bal, Hélène Dollfus, Anne Legrand, Roland Jaussaud, Tiffany Busa, Xavier Jeunemaitre, Catherine Petit, CHU Strasbourg, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Service Obstétrique [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre national de référence des maladies vasculaires rares, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Rouen, Normandie Université (NU), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Sorbonne Paris Cité (USPC), Centre régional de compétence des Maladies systémiques et auto-immunes rares de l'adulte et Maladies vasculaires rares, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Charles Sadron (ICS), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-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)-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), Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nanomédecine Régénérative (NanoRegMed), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Marseille, and Les Hôpitaux Universitaires de Strasbourg (HUS)
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Pathology, medicine.medical_specialty, Adolescent, 030105 genetics & heredity, Varicose Ulcer, Young Adult, 03 medical and health sciences, Aneurysm, Genetics, medicine, Tooth loss, Humans, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Aged, Periodontitis, Aortic dissection, Complement C1s, Complement C1r, business.industry, Middle Aged, medicine.disease, Hyperpigmentation, Abdominal aortic aneurysm, Dissection, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ehlers–Danlos syndrome, Child, Preschool, Mutation, Ehlers-Danlos Syndrome, Female, medicine.symptom, business, Aortic Aneurysm, Abdominal
Abstract: Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report thirteen novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.
Published: 2021
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4. Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling

Author: Lynn Pais, Anna Pelet, Wilhelmina S. Kerstjens-Frederikse, Christine Bole-Feysot, Yunia Sribudiani, Stanislas Lyonnet, Natasha Shur, Valérie Cormier-Daire, Louise Galmiche, Cécile Masson, Christopher T. Gordon, Chelsea Kois, Céline Huber, John A. Pugh, Simon Sadedin, Thuy-Linh Le, Nicolas Goudin, Tania Attié-Bitach, Susan M. White, Tiong Yang Tan, Geneviève Baujat, Valérie Serre, Xiaomin Dong, Mohammed Zarhrate, Patrick Nitschke, Jeanne Amiel, John Christodoulou, Frans W. Verheijen, Sophie Thomas, R Hofstra, Salima El Chehadeh, Valerie Mayne, Université Paris Cité (UPC), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Embryology and genetics of human malformation (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Molecular and Physiopathological bases of osteochondrodysplasia - Bases moléculaires et physiopathologiques des ostéochondrodysplasies (Equipe Inserm U1163), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Genetics and Development of the Cerebral Cortex (Equipe Inserm U1163), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Clinical Genetics
Subjects: 0301 basic medicine, Male, Models, Molecular, Developmental Disabilities, [SDV]Life Sciences [q-bio], HIRSCHSPRUNG DISEASE, INTRAFLAGELLAR TRANSPORT PROTEIN, ACTIVATION, 0302 clinical medicine, Neoplasms, Sonic hedgehog, Child, Genetics (clinical), Nuclear Proteins, PRIMARY CILIUM, Smoothened Receptor, Hedgehog signaling pathway, Cell biology, Pedigree, Child, Preschool, Female, Signal Transduction, Patched, Nerve Tissue Proteins, Biology, Zinc Finger Protein Gli2, Article, 03 medical and health sciences, HYPOTHALAMIC HAMARTOMA, Zinc Finger Protein Gli3, GLI2, Ciliogenesis, NERVOUS-SYSTEM DEVELOPMENT, Genetics, Humans, Hedgehog Proteins, Cilia, Hedgehog, Alleles, Base Sequence, SONIC HEDGEHOG, MUTATIONS, Infant, CILIARY, 030104 developmental biology, biology.protein, Smoothened, 030217 neurology & neurosurgery, GLI
Abstract: The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report biallelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.
Published: 2020
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5. 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
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6. Expanding the phenotypic spectrum of ARCN1-related syndrome

Author: Alyssa L. Ritter, Jessica Gold, Hiroshi Hayashi, Amanda M. Ackermann, Stephanie Hanke, Cara Skraban, Sanmati Cuddapah, Elizabeth Bhoj, Dong Li, Yukiko Kuroda, Jessica Wen, Ryojun Takeda, Audrey Bibb, Salima El Chehadeh, Amélie Piton, Jeanine Ohl, Mary K. Kukolich, Keisuke Nagasaki, Kohji Kato, Tomoo Ogi, Tricia Bhatti, Pierre Russo, Bryan Krock, Jill R. Murrell, Jennifer A. Sullivan, Vandana Shashi, Nicholas Stong, Hakon Hakonarson, Kentaro Sawano, Erin Torti, Rebecca Willaert, Yue Si, William Ross Wilcox, Katrine Verena Wirgenes, Kristian Thomassen, Katherine Carlotti, Angelika Erwin, Joanna Lazier, Thorsten Marquardt, Miao He, Andrew C. Edmondson, and Kosuke Izumi
Subjects: Hepatoblastoma, Male, Fetal Growth Retardation, Liver Neoplasms, Micrognathism, Dwarfism, Syndrome, Article, Cataract, Phenotype, Intellectual Disability, Humans, Female, Child, Genetics (clinical)
Abstract: PURPOSE: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. METHODS: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. RESULTS: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. CONCLUSION: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype–phenotype correlations are required.
Published: 2022

7. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author: James W. Wheless, Thierry Frebourg, Robert Olaso, Rosemarie Smith, Kelly Nori, François Lecoquierre, Delphine Héron, Roseline Caumes, Anne Boland, Ange-Line Bruel, Candy Kumps, Gaël Nicolas, Sarah Stewart, Sophie Rondeau, Diane Doummar, Marlène Rio, Giulia Barcia, Anne-Marie Guerrot, Gwenaël Le Guyader, Alexandra Afenjar, Sarah Vergult, Karine Poirier, Juliette Coursimault, Jennifer Morrison, Amy Kritzer, Anne-Sophie Alaix, Rebecca Hernan, Anne-Sophie Denommé-Pichon, Sabine Sigaudy, Christine Coubes, Pascale Saugier-Veber, Francisca Millan Zamora, Austin Larson, Michelle M. Morrow, Christine Poitou, Björn Menten, Mathilde Nizon, Thomas Smol, Elise Schaefer, Bénédicte Gérard, Charles Coutton, Salima El Chehadeh, Fanggeng Zou, Stéphanie Valence, Anita Shanmugham, Wendy K. Chung, Bert Callewaert, Christina Kresge, Arnold Munnich, Beth A. Pletcher, Laurence Faivre, Estelle Colin, Laurence Colleaux, Patricia G Wheeler, Annelies Dheedene, Frédéric Tran Mau-Them, Jean-François Deleuze, Claude Houdayer, Jeanne Amiel, Frédéric Bilan, Marine Tessarech, Bertrand Isidor, Guillaume Jouret, Cyril Mignot, Benjamin Cogné, Shuxi Liu, Boris Keren, Françoise Devillard, Catherine Schramm, Margaret Helm, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), GeneDx [Gaithersburg, MD, USA], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique médicale d’Alsace, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Sorbonne Université (SU), 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), CHU Grenoble, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Columbia University Irving Medical Center (CUIMC), University of Colorado Anschutz [Aurora], University of Tennessee System, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maine Medical Center, Arnold Palmer Hospital, Boston Children's Hospital, National Center of Genetics, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: Male, Bioinformatics, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, MESH: Child, Intellectual disability, Missense mutation, MESH: Obesity, MESH: Genetic Variation, MESH: Nerve Tissue Proteins, Child, Genetics (clinical), MESH: Genetic Association Studies, MESH: Heterozygote, 0303 health sciences, MESH: Transcription Factors, MESH: Infant, 3. Good health, Phenotype, MESH: Feeding and Eating Disorders, MESH: Young Adult, Child, Preschool, MESH: Epilepsy, Learning disability, Female, medicine.symptom, Adult, Heterozygote, Adolescent, Language delay, Nerve Tissue Proteins, Biology, MESH: Phenotype, MESH: Language Development Disorders, Feeding and Eating Disorders, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Language Development Disorders, Obesity, Genetic Association Studies, 030304 developmental biology, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Genetic Variation, Infant, MESH: Adult, medicine.disease, Human genetics, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Autism, MESH: Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.
Published: 2022
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8. Serpin B1 defect and increased apoptosis of neutrophils in Cohen syndrome neutropenia

Author: Laurence Duplomb, Jean-Noël Bastie, Edward Blair, Julie Riviere, Laurent Delva, Romain Da Costa, Arlette Hammann, Julien Thevenon, Bernard Aral, Jamal Ghoumid, Marie-Anne Gougerot-Pocidalo, Arnaud Lafon, Christel Thauvin-Robinet, Alain Schmitt, Patrick Edery, Virginie Carmignac, Julien Guy, Nathalie Droin, Eric Solary, Laurence Faivre, Gaëtan Jego, Laurence Dubrez, Jessica Racine, Salima El Chehadeh-Djebbar, François Girodon, and Claude Capron
Subjects: Adult, Male, Programmed cell death, Neutropenia, Adolescent, Neutrophils, Developmental Disabilities, Down-Regulation, Apoptosis, Fingers, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Drug Discovery, Myopia, Humans, Medicine, Obesity, Child, Serpins, Genetics (clinical), Cohen syndrome, biology, business.industry, Retinal Degeneration, SERPINB1, Middle Aged, medicine.disease, VPS13B, Child, Preschool, Neutrophil elastase, Mutation, Immunology, Microcephaly, biology.protein, Unfolded protein response, Muscle Hypotonia, Molecular Medicine, Female, business, 030215 immunology
Abstract: Cohen syndrome (CS) is a rare genetic disorder due to mutations in VPS13B gene. Among various clinical and biological features, CS patients suffer from inconsistent neutropenia, which is associated with recurrent but minor infections. We demonstrate here that this neutropenia results from an exaggerate rate of neutrophil apoptosis. Besides this increased cell death, which occurs in the absence of any endoplasmic reticulum stress or defect in neutrophil elastase (ELANE) expression or localization, all neutrophil functions appeared to be normal. We showed a disorganization of the Golgi apparatus in CS neutrophils precursors, that correlates with an altered glycosylation of ICAM-1 in these cells, as evidenced by a migration shift of the protein. Furthermore, a striking decrease in the expression of SERPINB1 gene, which encodes a critical component of neutrophil survival, was detected in CS neutrophils. These abnormalities may account for the excessive apoptosis of neutrophils leading to neutropenia in CS. KEY MESSAGES: Cohen syndrome patients' neutrophils display normal morphology and functions. Cohen syndrome patients' neutrophils have an increased rate of spontaneous apoptosis compared to healthy donors' neutrophils. No ER stress or defective ELA2 expression or glycosylation was observed in Cohen syndrome patients' neutrophils. SerpinB1 expression is significantly decreased in Cohen syndrome neutrophils as well as in VPS13B-deficient cells.
Published: 2019
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9. Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy

Author: Julien Thevenon, Sophie Blesson, Sylvie Manouvrier Hanu, Chloé Quélin, Florence Fellmann, Nicolas Chassaing, Fabienne Giuliano, Laetitia Lambert, Caroline Rooryck-Thambo, Pierre-Simon Jouk, Sylvie Di Filippo, Alexandre Vasiljevic, Christine Francannet, Daphné Lehalle, Audrey Putoux, Anna‐Gaëlle Giguet‐Valard, Sophie Naudion, Salima El Chehadeh, Estelle Colin, Viorica Ciorna‐Monferrato, Bruno Reversade, Lionel Van Maldergem, Fanny Morice-Picard, Renaud Touraine, Sébastien Moutton, Jocelyne Attia, Laurent Pasquier, A. Vigouroux-Castera, Catherine Yardin, Tania Attié-Bitach, Carine Abel, Hui Liu, Sylvie Odent, Christelle Cabrol, Florence Petit, Philippe Khau Van Kien, Thomas Simonet, Catherine Vincent-Delorme, Jean Chiesa, Juliette Piard, Anne Bazin, Mélanie Fradin, Bertrand Isidor, Loubna El Zein, Patrice Bouvagnet, Marie-Pierre Brechard, Emmanuelle Szenker-Ravi, Sophie Scheidecker, Claire Beneteau, and ACS - Heart failure & arrhythmias
Subjects: Heart Defects, Congenital, Male, midline anomaly, Heterozygote, medicine.medical_specialty, Genetic counseling, Consanguinity, Heterotaxy Syndrome, Biology, DNA sequencing, 03 medical and health sciences, consanguinity, Genetics, medicine, Humans, Family, Family history, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Fetus, Obstetrics, Homozygote, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, heterotaxy, congenital heart defects, Cardiac malformations, Pedigree, fetus, Parental consanguinity, Cytogenetic Analysis, Mutation, Female, next-generation sequencing, Heterotaxy
Abstract: Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.
Published: 2020

10. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long‐term outcome

Author: Rima Nabbout, Patrick Berquin, Sylvie Odent, Mathieu Kuchenbuch, Gwenaël Le Guyader, Marieke F. van Dooren, Jamel Chelly, Edor Kabashi, Melanie Jennesson, Giulia Barcia, Cyril Mignot, Tayeb Sekhara, Alexandra Afenjar, Marlène Rio, Anne Rolland, Claude Besmond, Andrés Rodríguez-Sacristán Cascajo, Gaetano Terrone, Isabelle Marey, Boris Keren, Alice Goldenberg, A.S. Lebre, Heather C Mefford, Gaetan Lesca, Anne de Saint Martin, Susanna Negrin, Nathalie Dorison, Hélène Maurey, Agnès Guët, David Geneviève, Marie Claire Y. de Wit, Jeremy L. Freeman, Pierre Meyer, Thierry Billette de Villemeur, Ingrid E. Scheffer, Katherine B. Howell, Anca Nica, Raphael Levy, Martino Montomoli, Renzo Guerrini, Elena Parrini, Candace T. Myers, Bertrand Isidor, Alice Poisson, Marion Gérard, Salima El Chehadeh, Lynette G. Sadleir, Julien Durigneux, Pascal Vrielynck, Amy L Schneider, Emmanuel Scalais, Laurence Hubert, Sophie Dupont, Vesna Brankovic, Damien Lederer, Hervé Isnard, Delphine Breuillard, Claire Bar, Alberto Danieli, Diane Doummar, Arnold Munnich, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Centre for the Diagnosis and management of genetic psychiatric disorders [Bron] (GénoPsy), Centre Hospitalier le Vinatier [Bron], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), CHU Rouen, Normandie Université (NU), CHU Amiens-Picardie, 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 génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pitié-Salpêtrière [AP-HP], FP7 Ideas: European Research Council, National Health and Medical Research Council, Health Research Council of New Zealand, ANR‐10-IAHU‐01, Agence Nationale de la Recherche, Fondation Bettencourt Schueller, 602531, Seventh Framework Programme, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR‐10IAHU‐01, Agence Nationale de la Recherche, Clinical Genetics, Neurology, and 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)
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Time Factors, Adolescent, autism spectrum disorders, [SDV]Life Sciences [q-bio], Encephalopathy, Severe epilepsy, Imaging data, Cohort Studies, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Shab Potassium Channels, drug-resistant epilepsy, Intellectual disability, medicine, Missense mutation, Humans, In patient, developmental and epileptic encephalopathy, Child, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Brain Diseases, sudden unexpected death in epilepsy, developmental encephalopathy, business.industry, Genetic Variation, Infant, Cognition, Electroencephalography, medicine.disease, potassium channels, 3. Good health, 030104 developmental biology, Treatment Outcome, Neurology, Child, Preschool, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association “KCNB1 France.” Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the longterm outcome in patients older than 12 years from our series and from literature. Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
Published: 2020
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11. A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum

Author: Anne-Sophie Guilbert, Charlie De Melo, Elise Schaefer, Benjamin Durand, Hélène Dollfus, Corinne Stoetzel, Nadège Calmels, Leonardo Donato, Dana Timbolschi, Nadine Kempf, Sophie Scheidecker, Dominique Astruc, Arnaud Sauer, Maria Cristina Antal, Salima El Chehadeh, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), 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)-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, and 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)
Subjects: 0301 basic medicine, Heart Defects, Congenital, Pathology, medicine.medical_specialty, Developmental Disabilities, Glaucoma, 030105 genetics & heredity, Osteochondrodysplasias, Craniofacial Abnormalities, 03 medical and health sciences, Camptodactyly, Megalocornea, Frank–ter Haar syndrome, Genetics, Medicine, Humans, Abnormalities, Multiple, Craniofacial, Genetics (clinical), Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Infant, Newborn, Infant, General Medicine, medicine.disease, Hypotonia, Buphthalmos, 030104 developmental biology, Phenotype, Invadopodia, Female, medicine.symptom, business
Abstract: Frank-ter Haar syndrome (FTHS) is a rare autosomal recessive syndrome resulting from mutations in the SH3PXD2B gene involved in the formation of podosomes and invadopodia which have a role in extracellular matrix remodelling and cell migration. FTHS is characterized by facial dysmorphism, megalocornea, inconstant glaucoma, variable developmental delay, skeletal and cardiac anomalies. To date, 40 patients have been reported in the literature with a clinical diagnosis of FTHS, only 20 patients having identified mutations. We present a review of these 20 reported patients and describe a patient born to non-consanguineous parents, with intrauterine growth retardation, hypotonia, congenital glaucoma, caudal appendix, scoliosis, camptodactyly, ventricular septal defect, thin corpus callosum and craniofacial features suggestive of FTHS. Clinical evolution resulted in buphthalmos worsening, coarsening of the facial features and respiratory failure leading to death at 4,5 months. Diagnosis was confirmed by the identification of a previously known homozygous mutation c.969delG, p.(Arg324Glyfs*19) in SH3PXD2B. This is the first description of very severe phenotype with lethal respiratory impairment in FTHS. Since very few patients are described in the literature, and 2 out of the 3 patients carrying the c.969delG mutation had a favourable clinical course, more cases are needed to better characterize the phenotype and understand the natural history of this syndrome. Furthermore, we hypothesize that the alteration of podosomes function could lead to a reduction of the extracellular matrix degradation and accumulation of the latter in the extracellular space, which might explain the coarsening of the facial features and the severe refractory glaucoma.
Published: 2020
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12. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability

Author: Florence Demurger, Christine Binquet, Muriel Holder, Frédéric Tran Mau-Them, Salima El Chehadeh, Martine Doco-Fenzy, Geneviève Baujat, Delphine Héron, Judith St-Onge, Christophe Philippe, Elodie Gautier, Robert Olaso, Rebecca A. Barnard, Paul Kuentz, François Lecoquierre, Stanislas Lyonnet, Gwenaëlle Collod-Béroud, Dominique Martin-Coignard, Isabelle Missotte, Anne Boland, Cyril Goizet, Laurence Perrin, Valérie Cormier-Daire, Sébastien Moutton, Nadine Hanna, Jean-François Deleuze, Audrey Putoux, Guillaume Jondeau, Sylvie Odent, Doris Lechner, Arnold Munnich, Thibaud Jouan, Aurélia Jacquette, Pierre-Simon Jouk, Martin Chevarin, Virginie Carmignac, Elisabetta Lapi, Alice Goldenberg, Christel Thauvin-Robinet, Sujatha Jagadeesh, P. Callier, Fatma Daoud, Yannis Duffourd, Frédéric Huet, Nathalie Marle, Charlotte Poe, Gipsy Lopez, Cyril Mignot, Florence Petit, Khadija Amarof, Brian J. O'Roak, Caroline Cabret, Fanny Morice-Picard, Jean Baptiste Rivière, Mirna Assoum, Marie Ange Delrue, Julien Thevenon, Laurence Faivre, David Geneviève, Elisabeth Sarrazin, Ange Line Bruel, Pauline Arnaud, Catherine Boileau, Christine Coubes, Didier Lacombe, Laurence Duplomb, Alice Masurel, Patrick Collignon, Antonio Vitobello, Julien Van-Gils, Bruno Leheup, Nolwenn Jean-Marçais, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Le Mans (CH Le Mans), CHU Pitié-Salpêtrière [AP-HP], Hôpital Robert Debré Paris, Hôpital Robert Debré, Hospices Civils de Lyon (HCL), CHU de la Martinique [Fort de France], Hôpital Pierre Zobda-Quitman [CHU de la Martinique], Centre hospitalier territorial Gaston-Bourret [Nouméa], CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire de Reims (CHU Reims), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Proband, Male, [SDV]Life Sciences [q-bio], intellectual deficiency, MESH: NFI Transcription Factors, chromatin remodeling, Marfan Syndrome, Craniofacial Abnormalities, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Mental Retardation, X-Linked, Exome, Child, de novo variants, Genetics (clinical), Exome sequencing, Genetics, MESH: Exome, MESH: Middle Aged, biology, MESH: Genetic Predisposition to Disease, Middle Aged, NFIX, MESH: Young Adult, Female, Adult, MESH: Mutation, Adolescent, Chromatin remodeling, MESH: Intellectual Disability, MESH: Marfan Syndrome, EHMT1, Young Adult, MESH: Whole Exome Sequencing, Intellectual Disability, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, marfanoid habitus, Gene, MESH: Neurodevelopmental Disorders, MESH: Adolescent, MESH: Humans, Genetic heterogeneity, MESH: Chromatin Assembly and Disassembly, MESH: Histone-Lysine N-Methyltransferase, MESH: Adult, Histone-Lysine N-Methyltransferase, medicine.disease, Chromatin Assembly and Disassembly, MESH: Male, NFI Transcription Factors, Neurodevelopmental Disorders, Mutation, biology.protein, Mental Retardation, X-Linked, MESH: Female
Abstract: PurposeMarfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.MethodsTo further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.ResultsWe identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.ConclusionWe demonstrated that DNVs were enriched in chromatin remodelling (p=2×10−4) and genes regulated by the fragile X mental retardation protein (p=3×10−8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
Published: 2019
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13. The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Author: Maria Nicla Loviglio, Thomas Arbogast, Aia Elise Jønch, Stephan C. Collins, Konstantin Popadin, Camille S. Bonnet, Giuliana Giannuzzi, Anne M. Maillard, Sébastien Jacquemont, Binnaz Yalcin, Nicholas Katsanis, Christelle Golzio, Alexandre Reymond, Christina Fagerberg, Charlotte Brasch Andersen, Martine Doco-Fenzy, Marie-Ange Delrue, Laurence Faivre, Benoit Arveiler, David Geneviève, Anouck Schneider, Marion Gerard, Joris Andrieux, Salima El Chehadeh, Elise Schaefer, Christel Depienne, Mieke Van Haelst, Eva H. Brilstra, Ellen Van Binsbergen, Jeske van Harssel, Lars T. van der Veken, James F. Gusella, Yiping Shen, Elyse Mitchell, Usha Kini, Lara Hawkes, Carolyn Campbell, Florence Niel Butschi, Marie-Claude Addor, Jacques S. Beckmann, Université de Lausanne = University of Lausanne (UNIL), Duke University [Durham], Lausanne University Hospital, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immanuel Kant Baltic Federal University (IKBFU), 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), 16p11.2 Consortium: Maria Nicla Loviglio, Aia Elise Jønch, Konstantin Popadin, Giuliana Giannuzzi, Anne M Maillard, Christina Fagerberg, Charlotte Brasch Andersen, Martine Doco-Fenzy, Marie-Ange Delrue, Laurence Faivre, Benoit Arveiler, David Geneviève, Anouck Schneider, Marion Gerard, Joris Andrieux, Salima El Chehadeh, Elise Schaefer, Christel Depienne, Mieke Van Haelst, Eva H Brilstra, Ellen Van Binsbergen, Jeske van Harssel, Lars T van der Veken, James F Gusella, Yiping Shen, Elyse Mitchell, Usha Kini, Lara Hawkes, Carolyn Campbell, Florence Niel Butschi, Marie-Claude Addor, Jacques S Beckmann, Sébastien Jacquemont, Alexandre Reymond., Dupuis, Christine, Amsterdam Reproduction & Development (AR&D), Human genetics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: Male, 0301 basic medicine, epistasis, Microcephaly, obesity, Embryo, Nonmammalian, Phosphoproteins/physiology, MAPK3, [SDV]Life Sciences [q-bio], Chromosome Disorders, Adaptor Proteins, Signal Transducing/genetics, zebrafish, Cohort Studies, Microcephaly/genetics, Mice, 0302 clinical medicine, Chromosome Disorders/genetics, Gene duplication, Genetics(clinical), Child, Zebrafish, Genetics (clinical), Aged, 80 and over, Mice, Knockout, Genetics, ZAP70, Brain, Gene Expression Regulation, Developmental, head size, Middle Aged, 16p11.2, Phenotype, Chromatin, [SDV] Life Sciences [q-bio], Child, Preschool, Knockout mouse, Female, Chromosomes, Human, Pair 16/genetics, Chromosome Deletion, Autistic Disorder/genetics, Signal Transduction, Adult, DNA Copy Number Variations, Adolescent, autism, Biology, Article, Young Adult, 03 medical and health sciences, Intellectual Disability, Zebrafish Proteins/genetics, medicine, Humans, Animals, Brain/metabolism, Autistic Disorder, Membrane Proteins/genetics, Adaptor Proteins, Signal Transducing, Aged, genome architecture, Membrane Proteins, Infant, Zebrafish Proteins, Phosphoproteins, medicine.disease, biology.organism_classification, Intellectual Disability/genetics, Mice, Inbred C57BL, 030104 developmental biology, Zebrafish/embryology, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery, Embryo, Nonmammalian/metabolism
Abstract: International audience; Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.
Published: 2017
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14. Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability

Author: Jean Donadieu, Delphine Héron, Laurence Faivre, Salima El Chehadeh, Daphné Lehalle, Claire Briandet, Elodie Gautier, Julien Thevenon, Daniel Amram, Thibaud Jouan, Jean-Baptiste Rivière, Judith Melki, Laurence Duplomb-Jego, Frédéric Huet, Christine Bellanné-Chantelot, Christel Thauvin-Robinet, Ange-Line Bruel, Yannis Duffourd, Lucile Pinson, Isabelle Maystadt, Judith St-Onge, Sophia Julia, Alexandra Gauthier-Vasserot, Paul Kuentz, Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), 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), CHU Dijon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Immuno-hématologie pédiatrique (MaRIH), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Université de Namur [Namur] (UNamur), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre hospitalier universitaire de Toulouse-Purpan, Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] ( IHOPe ), Hospices Civils de Lyon ( HCL ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service d’oncologie hématologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Immuno-hématologie pédiatrique ( MaRIH ), Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Namur, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de pédiatrie (CHU de Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Neutropenia, Adolescent, Neonatal onset, 03 medical and health sciences, 0302 clinical medicine, congenital neutropenia, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Intellectual Disability, Intellectual disability, Genetics, medicine, Congenital Bone Marrow Failure Syndromes, Humans, Exome, Child, Congenital Neutropenia, Genetic Association Studies, Genetics (clinical), Exome sequencing, Retrospective Studies, business.industry, High-Throughput Nucleotide Sequencing, Infant, Syndrome, medicine.disease, 3. Good health, Phenotype, 030104 developmental biology, CHD2, Child, Preschool, 030220 oncology & carcinogenesis, Cohort, Etiology, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers
Abstract: International audience; Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield of 40% (4/10). The results suggested that in many cases neutropenia and syndromic manifestations could not be assigned to the same molecular alteration. Three sub-groups of patients were highlighted: (i) severe, symptomatic chronic neutropenia, detected early in life, and related to a known mutation in the CN spectrum (ELANE); (ii) mild to moderate benign intermittent neutropenia, detected later, and associated with mutations in genes implicated in neurodevelopmental disorders (CHD2, HUWE1); and (iii) moderate to severe intermittent neutropenia as a probably undiagnosed feature of a newly reported syndrome (KAT6A). Unlike KAT6A, which seems to be associated with a syndromic form of CN, the other reported mutations may not explain the entire clinical picture. Although targeted gene sequencing can be discussed for the primary diagnosis of severe CN, we suggest that performing WES for the diagnosis of disorders associating CN with ID will not only provide the etiological diagnosis but will also pave the way towards personalized care and follow-up. (C) 2016 Wiley Periodicals, Inc., (C) 2016 John Wiley & Sons, Ltd
Published: 2016
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15. Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

Author: Anne Boland, Alain Verloes, Jean-François Deleuze, Amélie Piton, Robert Olaso, Jean-Louis Mandel, Laura Mary, Laurence Faivre, Christine Coubes, Bénédicte Gérard, Elise Schaefer, David Geneviève, Claire Feger, Irina Giurgea, Estelle Colin, Francesca Mattioli, Salima El Chehadeh, Dana Timbolschi, Yline Capri, Jennifer Fabre-Teste, Elsa Nourisson, Elisabeth Flori, Magalie Barth, Laurence Perrin, Claire Redin, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Collège de France (CdF (institution)), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), 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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service de cytogénétique, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Génotypage, Institut de Génomique, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], 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 Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des maladies génétiques d'expression pédiatrique, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Intellectual disability, Disease, 030105 genetics & heredity, Bioinformatics, medicine.disease_cause, Transcription Factor 4, MESH: Young adult, MESH: Child, Hyperventilation, 10. No inequality, Child, MESH: Transcription factor 4 / genetics, Genetics (clinical), MESH: Hyperventilation / genetics, Sanger sequencing, Mutation, High-Throughput Nucleotide Sequencing, TCF4, 3. Good health, Phenotype, MESH: Facies, Child, Preschool, Cohort, symbols, Female, MESH: Hight-throughput Nucleotide sequencing, Adult, MESH: Mutation, Adolescent, MESH: Phenotype, Article, MESH: Child, preschool, 03 medical and health sciences, symbols.namesake, Young Adult, Genetics, medicine, Humans, MESH: Adolescent, MESH: Humans, MESH: Hyperventilation / diagnosis, business.industry, Facies, MESH: Adult, medicine.disease, MESH: Male, MESH: Intellectual Disability / pathology, Human genome, business, Large-Scale Sequencing, MESH: Female
Abstract: IF 3.636 (2017); International audience; High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt–Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.
Published: 2018
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16. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Author: Olivier Vanakker, Maria Kirchhoff, Christian Gilissen, Jenny Morton, Ineke van der Burgt, Kelly Radtke, Tugce Aktas, Sarah Vergult, Diana Johnson, Tobias Rumpf, Tony Roscioli, André Reis, Alan Fryer, Salima El Chehadeh, Christel Thauvin-Robinet, Ange Line Bruel, Rolph Pfundt, Sander Pajusalu, David Francis, Asifa Akhtar, Iben Bache, Tiong Yang Tan, Vera M. Kalscheuer, Meredith Wilson, Björn Menten, Giuseppe Semplicio, Julien Thevenon, Richard Fisher, Yannis Duffourd, Gerhard Mittler, Witold G. Szymanski, M. Felicia Basilicata, Victoria McKay, Kristin Lindstrom, Han G. Brunner, Katrin Õunap, Jaya Ganesh, Claudia Isabelle Keller Valsecchi, Megan T. Cho, Laurence Faivre, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Copenhagen University Hospitals, Radboud University Medical Center [Nijmegen], Center for Medical Genetics [Ghent], Ghent University Hospital, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], GeneDx [Gaithersburg, MD, USA], Murdoch Children's Research Institute (MCRI), Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Sheffield Children's NHS Foundation Trust, Liverpool Women's NHS Foundation Trust, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), and 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 [2016-2019] (UGA [2016-2019])
Subjects: Male, 0301 basic medicine, CHROMATIN, INTELLECTUAL DISABILITY, Chromosomal Proteins, Non-Histone, CHROMOSOME, Cohort Studies, Histones, Mice, Genes, X-Linked, MSL complex, Child, Cells, Cultured, Histone Acetyltransferases, Epigenomics, Acetylation, Genetic Diseases, X-Linked, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Chromatin, Cell biology, DNA-Binding Proteins, DROSOPHILA, Histone, ACETYLTRANSFERASE, Child, Preschool, Female, Adolescent, Mice, Transgenic, Biology, Article, Histone H4, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Genetics, Animals, Humans, CELL-CYCLE, Epigenetics, DEACETYLASE, MOF, MSL3, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DOSAGE COMPENSATION COMPLEX, Infant, Dosage compensation complex, PROTEIN INTERACTIONS, HEK293 Cells, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Case-Control Studies, Mutation, biology.protein, Histone deacetylase, Protein Processing, Post-Translational, Transcription Factors, Ultra-rare developmental disorders
Abstract: International audience; The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.
Published: 2018
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17. Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses

Author: Judith St-Onge, Anne-Laure Mosca-Boidron, Thibaud Jouan, Frédéric Tran-Mau-Them, Ange-Line Bruel, Laetitia Lambert, Sebastien Moutton, Aurélie Bourchany, Nolwenn Jean, Aurélia Jaquette, Christel Thauvin-Robinet, Daphné Lehalle, Elise Schaefer, Nada Houcinat, Charlotte Poe, Yannis Duffourd, Paul Kuentz, Salima El Chehadeh-Djebbar, Alice Masurel-Paulet, Martin Chevarin, Laurence Faivre, Sophie Nambot, Marjorie Willems, Mathilde Lefebvre, Nicole Laurent, Antonio Vitobello, Frédéric Huet, Julien Thevenon, Patrick Callier, Jean-Baptiste Rivière, Christophe Philippe, 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 ), Service de pédiatrie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD, Département de Génétique Clinique [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service de Génétique Médicale, Hôpital Civil, Strasbourg, Centre de Génétique (Hôpital de la Pitié-Salpétrière, Paris), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Service de Pathologie [CHU de 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-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), FHU TRANSLAD (CHU de Dijon), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Adult, Male, Exome sequencing, medicine.medical_specialty, Time Factors, Adolescent, Genetic counseling, Bioinformatics, Turnaround time, Sensitivity and Specificity, Undiagnosed genetic conditions, 03 medical and health sciences, Genetics, medicine, Humans, Exome, Genetic Testing, Medical diagnosis, Intensive care medicine, Child, Genetics (clinical), Genetic testing, Whole genome sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, medicine.diagnostic_test, business.industry, Infant, Newborn, Infant, General Medicine, Sequence Analysis, DNA, Diagnostic turnaround time, 3. Good health, Clinical trial, 030104 developmental biology, Early Diagnosis, Child, Preschool, Female, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: IF 2.137; International audience; BACKGROUND AND OBJECTIVE:Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results.METHODS:WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation.RESULTS:The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials.CONCLUSIONS:This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Published: 2017
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18. Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

Author: Montserrat Rodríguez-Ballesteros, Laurence Faivre, Pierre-Simon Jouk, Christine Francannet, Damien Sanlaville, Sophie Naudion, Hélène Dollfus, Nicole Philip, Pierre Sarda, Marine Legendre, X. Piguel, Alice Masurel-Paulet, Marie-Ange Delrue, Frédéric Bilan, Aurélia Jacquette, Dominique Bonneau, Catherine Vincent-Delorme, Valérie Layet, Michèle Mathieu-Dramard, Delphine Héron, Sébastien Moutton, Alice Goldenberg, Sophie Julia, Sophie Blesson, Sylvie Odent, Philippe Parent, Chloé Quélin, Estelle Colin, Mélanie Fradin, Anne-Marie Guerrot, David Geneviève, Lucile Pinson, Renaud Touraine, Sabine Sigaudy, Stéphanie Ragot, Didier Lacombe, Massimiliano Rossi, Salima El Chehadeh, Tiffany Busa, Annick Toutain, Stanislas Lyonnet, Véronique Abadie, Bruno Leheup, Dominique Martin-Coignard, Tania Attié-Bitach, Brigitte Gilbert-Dussardier, Sandra Mercier, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique clinique [Poitiers], Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Santé mentale et santé publique (SMSP - U1178), Université Paris-Sud - Paris 11 (UP11)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale et Génomique Fonctionnelle (GMGF), 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 National de la Recherche Scientifique (CNRS), 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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), 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), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Le Mans (CH Le Mans), 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), 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) (AP-HP)-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), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université 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), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, 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), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service Endocrinologie [CHU Poitiers], Service Génétique Médicale [CHU Poitiers], French Ministry of Health ID-RCB: 2010-A00700-39, Santé mentale et santé publique ( SMSP - U1178 ), Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hopital Necker-Enfants Malades-Assistance publique - Hôpitaux de Paris (AP-HP), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), 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 National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Médecine Aérospatiale du Service de Santé des Armées ( IMASSA ), Service de Santé des Armées, Université d'Angers ( UA ) -CHU Angers, 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 ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Bretonneau-CHRU Tours, Epidémiologie et anlyses en santé publique: risques, maladies chroniques et handicaps, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique médicale et cytogénétique [Le Mans], CH Le Mans, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CLAD Ouest, Centre Hospitalier Universitaire [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 ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, CHU - HÔTEL-DIEU Clermont-Ferrand, CHU Bordeaux [Bordeaux], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), 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)-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 ), Service de Pédiatrie et de Génétique Médicale, Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, 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 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Cardiologie, Pôle DUNE, CHU de Poitiers, Centre d' investigation clinique-plurithématique du CHU de Poitiers, Génétique Médicale, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Médecine Aérospatiale du Service de Santé des Armées (IMASSA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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 ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, université de Bourgogne, GAD, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), 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, Central Nervous System, Male, update, Choanal atresia, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, Gastroenterology, spectrum, Cohort Studies, CHARGE syndrome, Genotype, Medicine, Child, Genetics (clinical), Coloboma, Genetic disorder, Cranial Nerves, Hypoplasia, 3. Good health, DNA-Binding Proteins, Phenotype, Molecular Diagnostic Techniques, Child, Preschool, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Anosmia, 03 medical and health sciences, Young Adult, Internal medicine, Genetics, otorhinolaryngologic diseases, Humans, Abnormalities, Multiple, Genetic Testing, Alleles, Genetic Association Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, association, DNA Helicases, Infant, medicine.disease, mutations, diagnostic-criteria, 030104 developmental biology, Amino Acid Substitution, Atresia, chd7 gene, proposal, CHARGE Syndrome, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (2006). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.
Published: 2017
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19. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

Author: Patrick Callier, Angélique Quartier, Matthieu Jung, Brigitte Gilbert-Dussardier, Vincent des Portes, Claire Feger, Bernard Jost, Bénédicte Gérard, Stéphanie Le Gras, Daphné Lehalle, Elsa Nourisson, Anne-Sophie Casteleyn, Claire Redin, Julien Thevenon, Anne-Laure Mosca-Boidron, Laurence Faivre, Hélène Poquet, Frédéric Huet, Paul Kuentz, Christel Thauvin-Robinet, Véronique Geoffroy, Jean-Louis Mandel, Massimiliano Rossi, Gaetan Lesca, Alice Masurel, Patrick Edery, Benoit Trojak, Salima El Chehadeh, Stéphanie Maury, Jean Muller, Amélie Piton, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de Génétique Moléculaire [CHRU Strasbourg], CHRU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cytogénétique (CHU de Dijon), Service de psychiatrie générale et addictologie [CHU de Dijon], French Ministry of Health Fondation Jerome Lejeune Agence de la Biomedecine, CREGEMES Agence Nationale de la Recherche MENESR et Fondation Recherche Medicale Regional Council of Burgundy, ANR-10-IDEX-0002,UNISTRA,UNISTRA(2010), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and ANR-10-IDEX-0002-02/10-IDEX-0002,UNISTRA,UNISTRA ( 2010 )
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, diagnosis, RNA Splicing, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Fragile X Mental Retardation Protein, 03 medical and health sciences, Exon, Genetic linkage, placebo-controlled trial, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Molecular genetics, Genetics, medicine, Humans, gene, Genetics (clinical), Mutation, intron 10, Siblings, Middle Aged, medicine.disease, FMR1, Human genetics, 3. Good health, Fragile X syndrome, developmental delay, of-the-literature, 030104 developmental biology, intellectual disability, Fragile X Syndrome, mental-retardation, Medical genetics, Female, point mutation, double-blind, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G > A (family 2) and a maternally inherited c.420-8A > G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.
Published: 2017
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20. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Author: Estelle Colin, Christel Thauvin-Robinet, Bernard Jost, Hélène Dollfus, Marie-Ange Delrue, Dominique Bonneau, Marjolaine Willems, Christine Francannet, Claire Feger, Michèle Mathieu-Dramard, Patrick Edery, Martine Doco-Fenzy, Laurence Olivier-Faivre, Véronique Geoffroy, Jean-Louis Mandel, Muriel Philipps, Serge Vicaire, Bérénice Doray, Alice Goldenberg, Magalie Barth, Julien Thevenon, Julia Lauer, Didier Lacombe, Gaetan Lesca, David Geneviève, Angélique Quartier, Dominique Martin-Coignard, Yvan Herenger, Serge Lumbroso, Salima El-Chehadeh, Bénédicte Gérard, Mélanie Fradin, Gilles Morin, Jean Muller, Yves Alembik, Sylvie Sukno, Amélie Piton, Nicolas Haumesser, Claire Redin, Bertrand Isidor, Elisabeth Flori, Valérie Drouin-Garraud, Pierre Sarda, Alice Masurel-Paulet, Michael Dumas, Stéphanie Le Gras, and Anne Polge
Subjects: Adult, Male, Adolescent, DNA Mutational Analysis, autism, Biology, DNA sequencing, Young Adult, Intellectual disability, Genetics, medicine, Humans, Child, Genetics (clinical), ATRX, causative, Genetic heterogeneity, Infant, Newborn, high-throughput sequencing, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Molecular diagnostics, medicine.disease, FMR1, Molecular Diagnostic Techniques, intellectual disability, Child, Preschool, Autism, Cognitive and Behavioural Genetics, Female, CUL4B, mutation
Abstract: Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.
Published: 2014

21. Congenital neutropenia with retinopathy, a new phenotype without intellectual deficiency or obesity secondary toVPS13Bmutations

Author: Julien Thevenon, Judith St-Onge, Bernard Aral, Patrick Callier, Salima El Chehadeh, Pierre Sarda, Christian P. Hamel, Virginie Carmignac, Frédéric Huet, Nathalie Droin, Lucie Gueneau, Laurence Duplomb, Christel Thauvin-Robinet, Laurence Faivre, and Nadège Gigot
Subjects: Adult, Pathology, medicine.medical_specialty, Microcephaly, Neutropenia, DNA Mutational Analysis, Vesicular Transport Proteins, medicine.disease_cause, Retinal Diseases, Intellectual Disability, Gene Order, Genetics, medicine, Congenital Bone Marrow Failure Syndromes, Humans, Obesity, Congenital Neutropenia, Genetics (clinical), Mutation, Cohen syndrome, business.industry, Facies, Syndrome, medicine.disease, Phenotype, Pedigree, VPS13B, Female, business, Retinopathy
Abstract: Over one hundred VPS13B mutations are reported in Cohen syndrome (CS). Most cases exhibit a homogeneous phenotype that includes intellectual deficiency (ID), microcephaly, facial dysmorphism, slender extremities, truncal obesity, progressive chorioretinal dystrophy, and neutropenia. We report on a patient carrying two VPS13B splicing mutations with an atypical phenotype that included microcephaly, retinopathy, and congenital neutropenia, but neither obesity nor ID. RNA analysis of the IVS34+2T_+3AinsT mutation did not reveal any abnormal splice fragments but mRNA quantification showed a significant decrease in VPS13B expression. RNA sequencing analysis up- and downstream from the IVS57+2T>C mutation showed abnormal splice isoforms. In contrast to patients with typical CS, who express only abnormal VPS13B mRNA and truncated protein, a dose effect of residual normal VPS13B protein possibly explains the incomplete phenotype in the patient. This observation emphasizes that VPS13B analysis should be performed in cases of congenital neutropenia associated with retinopathy, even in the absence of ID, therefore extending the VPS13B phenotype spectrum. © 2013 Wiley Periodicals, Inc.
Published: 2013
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22. Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

Author: Charles Coutant, Laurent Arnould, Christophe Philippe, Patrick Callier, Pierre Fumoleau, Myriam Bronner, Emmanuelle Ferrant, Sarab Lizard, Amandine Baurand, Jean-Louis Jouve, Laurence Faivre, Carole Chery, Gérard Couillault, Alexandra Delignette, Catherine Loustalot, Caroline Chapusot, Côme Lepage, Thierry Frebourg, Emilie Degrolard-Courcet, Laurent Martin, Francine Mugneret, Marie-Martine Padeano, Salima El Chehadeh, Séverine Guiu, Philippe Jonveaux, Fanny Coron, Joanna Sokolowska, Cyril Hatem, Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de chirurgie [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Polyclinique du Parc - Clinique Drevon [Dijon], Service d'Hématologie Clinique (CHU de Dijon), Service de pédiatrie (CHU de Dijon), Service de radiologie [Centre Georges-François Leclerc], Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], UNICANCER, Laboratoire de cytogénétique (CHU de Dijon), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: Adult, Biallelic Mutation, RNA Splicing, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Biology, medicine.disease_cause, Article, Frameshift mutation, Genetics, medicine, Humans, Missense mutation, Age of Onset, Gene, Alleles, Genetics (clinical), BRCA2 Protein, Mutation, Point mutation, Computational Biology, Chromosome Breakage, Pedigree, 3. Good health, Amino Acid Substitution, Female, RNA Splice Sites, Chromosome breakage, Colorectal Neoplasms
Abstract: International audience; Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.
Published: 2013
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23. Changing facial phenotype in Cohen syndrome

Author: Bernard Aral, Nadège Gigot, François-Guillaume Debray, Alice Masurel-Paulet, Patrick Rump, Christel Thauvin-Robinet, Frédéric Huet, Muriel Holder-Espinasse, Marlène Rio, Laurence Duplomb, Patrick Callier, Edward Blair, Anne-Marie Frances, Salima El Chehadeh-Djebbar, Anne Moncla, and Laurence Faivre
Subjects: Male, Microcephaly, Developmental Disabilities, FEATURES, facial phenotype, Vesicular Transport Proteins, Myopia, CRITERIA, HETEROGENEITY, Child, Genetics (clinical), Genetics, Cohen syndrome, Retinal Degeneration, Hypotonia, VPS13B, Phenotype, medicine.anatomical_structure, Child, Preschool, Muscle Hypotonia, Female, medicine.symptom, medicine.medical_specialty, changing phenotype, Genetic counseling, Biology, Article, Fingers, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, Obesity, Short philtrum, Auricle, NATURAL-HISTORY, medicine.disease, Dermatology, MUTATIONAL SPECTRUM, GENE, DELETIONS, stomatognathic diseases, Early Diagnosis, Face, Mutation, Square face, VPS13B gene
Abstract: Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.
Published: 2013
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24. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

Author: Matthieu P. Robert, Salima El Chehadeh, Geert Vandeweyer, Candace Bensignor, Wilhelmina S. Kerstjens-Frederikse, Darina Prchalova, Hélène Dollfus, Jean-Baptiste Rivière, Christel Thauvin-Robinet, Paul Kuentz, Edwin Reyniers, Patrick Calvas, Caroline Bonnet, Marketa Havlovicova, Rodica Isaiko, Vincent Laugel, Nicolas Chassaing, Julien Thevenon, Christian Gilissen, Morgane Straub, Laurence Faivre, Yannis Duffourd, Miroslava Hancarova, Bart Loeys, R. Frank Kooy, Ange-Line Bruel, Rolph Pfundt, Catherine Creuzot-Garcher, Jolien S. Klein Wassink-Ruiter, Zdenek Sedlacek, FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Service de pédiatrie (CHU de Dijon), Service d'Ophtalmologie (CHU de Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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), CHU Strasbourg, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Service de Cardiologie, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, MESH: Heart Defects, Congenital / physiopathology, Microcephaly, Pathology, MESH: Heart Defects, Congenital / genetics, MESH: Exome / genetics, 030105 genetics & heredity, MESH: RNA Splicing / genetics, Microphthalmia, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Exome, MESH: RNA Splicing Factors / genetics, Child, Frameshift Mutation, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), Exome sequencing, Coloboma, MESH: Frameshift Mutation, High-Throughput Nucleotide Sequencing, Microdeletion syndrome, Microcephaly, Verheij syndrome, PUF60, Chemistry, Phenotype, Child, Preschool, DISEASES, Medical genetics, Female, RNA Splicing Factors, medicine.symptom, Chromosome Deletion, Chromosomes, Human, Pair 8, MESH: Dwarfism / genetics, Heart Defects, Congenital, medicine.medical_specialty, GENES, Adolescent, RNA Splicing, MESH: Chromosome Deletion, Dwarfism, Biology, MESH: Phenotype, Short stature, Article, PUF60, 03 medical and health sciences, Internal medicine, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Genetics, medicine, Humans, Craniofacial, MESH: Adolescent, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MESH: Humans, MESH: Child, Preschool, medicine.disease, MESH: Repressor Proteins / genetics, MESH: Male, Repressor Proteins, 030104 developmental biology, Endocrinology, MESH: Chromosomes, Human, Pair 8 / genetics, MESH: Dwarfism / physiopathology, MESH: Intellectual Disability / physiopathology, Human medicine, MESH: Intellectual Disability / genetics, Verheij syndrome, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Item does not contain fulltext Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.
Published: 2017
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25. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Author: Seana O'Regan, Tiziana Mongini, Céline Buon, Anne Marie Beaufrere, Yoshiteru Azuma, Bertrand Fontaine, Hanns Lochmüller, S. Bauche, Ana Töpf, Chiara Fiorillo, Jean-François Deleuze, E. Lacène, Julien Thevenon, Gisèle Bonne, Damien Sternberg, C. Burloiu, Yannis Duffourd, Isabelle Desguerre, Isabelle Nelson, Guy Brochier, Anne Boland, Benoit Bœuf, Michèle Mayer, Laure Strochlic, Jocelyn Laporte, Laurence Faivre, Sophie Nicole, Ganaelle Remerand, Céline Pebrel-Richard, Laurent Servais, Federica Ricci, Guja Astrea, Doris Lechner, Salima El Chehadeh-Djebbar, Nassima Bouzidi, Fanny Laffargue, Bruno Eymard, Marie Christine Nougues, Norma B. Romero, Grace McMacken, Carmen Sandu, Niculina Butoianu, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Newcastle University [Newcastle], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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) (AP-HP)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Université Bourgogne Franche-Comté [COMUE] (UBFC), FHU TRANSLAD, Département de Génétique, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Università degli studi di Torino = University of Turin (UNITO), Università degli studi di Genova = University of Genoa (UniGe), 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 [APHP], Service de Génétique Médical, CHU Pitié-Salpêtrière [APHP], Unité de Morphologie Neuromusculaire, 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 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)-CHU Pitié-Salpêtrière [APHP], 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), Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Albert Einstein College of Medicine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatriques et maladies du dévéloppement, Service de neuropédiatrie [Trousseau], AFM-Telethon 20030Fondation Maladies Rares within the Myocapture sequencing project Medical Research Council UK G1002274 98482 European Union Seventh Framework Programme (FP7) 305444 305121, [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), ANR-10-INBS-09-01/10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), 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 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Albert Einstein College of Medicine [New York], 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), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), 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], and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Male, Apnea, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, receptors, respiratory rhythm, Compound heterozygosity, Synaptic Transmission, 0302 clinical medicine, Genetics(clinical), Exome, neurotransmission, Child, Genetics (clinical), Arthrogryposis, Muscle Weakness, Symporters, Homozygote, deficiency, Congenital myasthenic syndrome, Hypotonia, Cholinergic Neurons, 3. Good health, medicine.anatomical_structure, acetyltransferase, Child, Preschool, butyrylcholinesterase, Muscle Hypotonia, Female, medicine.symptom, medicine.medical_specialty, Heterozygote, Adolescent, Mutation, Missense, Neuromuscular Junction, Presynaptic Terminals, Genes, Recessive, Butyrylcholinesterase, HEK293 Cells, Humans, Infant, Infant, Newborn, Mutation, Myasthenia Gravis, Genetics, Neuromuscular junction, 03 medical and health sciences, neuromuscular-junction, Internal medicine, Report, expression, medicine, Recessive, Cholinergic neuron, Preschool, business.industry, Muscle weakness, Newborn, medicine.disease, mutations, Choline transporter, 030104 developmental biology, Endocrinology, Genes, Cholinergic, Missense, business, knockout mouse, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMS5), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
Published: 2016
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26. Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing

Author: Judith St-Onge, Yannis Duffourd, Sandra Whalen, Marjolaine Willems, Anne-Claire Bursztejn, Massimiliano Rossi, Bertrand Isidor, Patrick Edery, Odile Boute, Virginie Carmignac, J. Miquel, Sébastien Barbarot, Daniel Amram, Fanny Morice-Picard, A. Phan, Pierre Vabres, Didier Lacombe, Maryse Bonnière, Jean-Baptiste Rivière, Nadia Bahi-Buisson, Catherine Vincent-Delorme, Thibaud Jouan, Paul Kuentz, Caroline Michot, Renaud Touraine, Jean-Benoît Courcet, Christine Francannet, Marie Vincent, Smail Hadj-Rabia, Valérie Cormier-Daire, Christine Coubes, Cyril Mignot, Nathalie Marle, Jeanne Amiel, Michèle Mathieu-Dramard, Philippe Khau Van Kien, Juliette Mazereeuw-Hautier, Annabel Maruani, Salima El Chehadeh, Geneviève Baujat, Christine Chiaverini, Daphné Lehalle, Arthur Sorlin, Florence Petit, Bruno Delobel, Laurence Faivre, Julien Thevenon, Stéphanie Arpin, Didier Bessis, Damien Haye, David Geneviève, Tania Attié-Bitach, Claire Abasq-Thomas, Jelena Martinovic, Alain Verloes, Christel Thauvin-Robinet, Juliette Albuisson, Marie-Line Jacquemont, Alice Goldenberg, Olivia Boccara, and Ludovic Martin
Subjects: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Genotype, Class I Phosphatidylinositol 3-Kinases, Prenatal diagnosis, Bioinformatics, medicine.disease_cause, DNA sequencing, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Prenatal Diagnosis, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Allele, Child, Genetics (clinical), Alleles, Genetic Association Studies, Growth Disorders, Genetic testing, Mutation, medicine.diagnostic_test, business.industry, Mosaicism, Infant, Newborn, Disease Management, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Phenotype, 030104 developmental biology, Amino Acid Substitution, Child, Preschool, Allelic heterogeneity, Female, business, 030217 neurology & neurosurgery
Abstract: Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10−5). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10−25), regardless of the phenotype. Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions. Genet Med advance online publication 02 February 2017
Published: 2016

27. Mutations in the ERCC2 (XPD) gene associated with severe fetal ichthyosis and dysmorphic features

Author: Marguerite, Miguet, Julien, Thevenon, Vincent, Laugel, Mathilde, Lefebvre, Aurélie, Bourchany, Jean-Baptiste, Rivière, Yannis, Duffourd, Elise, Schaefer, Maria Cristina, Antal, Rosalie, Abida, Anne-Sophie, Weingertner, Valérie, Kremer, Pierre, Vabres, Fanny, Morice-Picard, Marie, Gonzales, Dan, Lipsker, Sylvie, Fraitag, Jean-Louis, Mandel, Jamel, Chelly, Hélène, Dollfus, Laurence, Faivre, Christel, Thauvin-Robinet, Nadège, Calmels, and Salima, El Chehadeh
Subjects: Craniofacial Abnormalities, Male, Pregnancy, Mutation, Humans, Ichthyosis, Trichothiodystrophy Syndromes, Female, Gestational Age, Fetal Death, Xeroderma Pigmentosum Group D Protein
Published: 2016

28. Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

Author: Julien Thevenon, Céline Souchay, Gail K Seabold, Inna Dygai-Cochet, Patrick Callier, Sébastien Gay, Lucie Corbin, Laurence Duplomb, Christel Thauvin-Robinet, Alice Masurel-Paulet, Salima El Chehadeh, Magali Avila, Delphine Minot, Eric Guedj, Sophie Chancenotte, Marlène Bonnet, Daphne Lehalle, Ya-Xian Wang, Paul Kuentz, Frédéric Huet, Anne-Laure Mosca-Boidron, Nathalie Marle, Ronald S Petralia, Laurence Faivre, 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), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire d'Etude de l'Apprentissage et du Développement [Dijon] (LEAD), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB), Neurochem lab (NIDCD), Nationale Institute of Health, Service de Médecine Nucléaire, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre Hospitalier Chalon-sur-Saône William Morey, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Référent des Troubles du Langage et des Apprentissages [CHU Dijon] (CRTLA ), Laboratoire de cytogénétique (CHU de Dijon), Regional council of Burgundy NIDCD/NIH, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire d'Etude de l'Apprentissage et du Développement [Dijon] ( LEAD ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Neurochem lab ( NIDCD ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Reference Troubles Langages & Apprentissages, IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Hôpital de la Timone [CHU - APHM] (TIMONE), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Candidate gene, family, speech, Hippocampal formation, Rats, Sprague-Dawley, 0302 clinical medicine, Borderline intellectual functioning, Neuropsychological assessment, Child, disorders, Genetics (clinical), Cells, Cultured, adhesion-like molecules, Membrane Glycoproteins, medicine.diagnostic_test, Learning Disabilities, Brain, Magnetic Resonance Imaging, 3. Good health, Pedigree, Memory, Short-Term, Brain size, Female, Adult, Heterozygote, nmda receptor, autism, Nerve Tissue Proteins, Biology, Receptors, N-Methyl-D-Aspartate, Article, 03 medical and health sciences, Fluorodeoxyglucose F18, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, expression, Genetics, medicine, Animals, Humans, Memory Disorders, language, Genetic heterogeneity, Working memory, Membrane Proteins, down-syndrome, Rats, 030104 developmental biology, Endophenotype, Positron-Emission Tomography, Synapses, short-term, Radiopharmaceuticals, Neuroscience, 030217 neurology & neurosurgery, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.
Published: 2016
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29. 9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping

Author: Laurence Faivre, Marie-Ange Delrue, Nathalie Marle, Fanny Morice-Picard, Pierre-Simon Jouk, Delphine Héron, Alice Goldenberg, Stéphanie Perez-Martin, Julien Thevenon, Frédéric Huet, Véronique Dulieu, Alice Masurel, Patricia Calenda, Patrick Callier, Salima El Chehadeh, Sylvie Manouvrier-Hanu, Sophie Dupuis-Girod, Pascale Saugier-Veber, Gipsy Billy-Lopez, Joris Andrieux, Paul Kuentz, Ghislaine Plessis, Christel Thauvin-Robinet, Géraldine Joly-Helas, Sophie Nambot, Mathilde Lefebvre, Charles Coutton, Anne-Laure Mosca-Boidron, Caroline Rooryck, 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 ), Service de Cardiologie, Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire de cytogénétique (CHU de Dijon), Pôle Rééducation - Réadaptation (Médecine Physique et Réadaptation) (CHU de Dijon), Service de pédiatrie (CHU de Dijon), EDF ( EDF ), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( 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 ), Centre Hospitalier Universitaire [Grenoble] ( CHU ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-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, Maladies Rares - Génétique et Métabolisme ( MRGM ), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux], Service de génétique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique, Hospices Civils de Lyon ( HCL ) -Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Groupe Hospitalier Est, Regional council of Burgundy, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, EDF (EDF), Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), 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]), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Maladies Rares - Génétique et Métabolisme (MRGM), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupe Hospitalier Est, IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: 0301 basic medicine, Male, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Haploinsufficiency, cerebral hypomyelination, west-syndrome, Bioinformatics, Craniofacial Abnormalities, 0302 clinical medicine, Intellectual disability, STXBP1, Child, Genetics (clinical), Nail patella syndrome, Genetics, Endoglin, Syndrome, 3. Good health, developmental delay, Phenotype, intellectual disability, Medical genetics, Female, Chromosome Deletion, Chromosomes, Human, Pair 9, medicine.medical_specialty, Adolescent, LIM-Homeodomain Proteins, Biology, Contiguous gene syndrome, Article, 03 medical and health sciences, Munc18 Proteins, Genetic linkage, medicine, Humans, de-novo mutations, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, disease, Epilepsy, infantile epileptic encephalopathy, association, deletions, medicine.disease, Human genetics, 030104 developmental biology, nail-patella syndrome, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novo overlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1B and the ENG genes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1 within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1B deletion, epistaxis and cutaneousmucous telangiectasias explained by ENG haploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.
Published: 2016
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30. The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Author: Albert David, Chloé Quélin, Clarisse Baumann-Morel, Eric Bieth, Bruno Dumont, Judith Melki, Elise Shaeffer, Yves Alembik, Fabienne Giuliano, Christel Thauvin, Nicolas Chassaing, Sophie Julia, Anne-Lise Delezoide, Marine Lebrun, Tiffany Busa, Geneviève Baujat, David Geneviève, Séverine Audebert, Yline Capri, Patricia Blanchet, Martine Le Merrer, Sandrine Marlin, Mouna Barat-Houari, Marianne Till, Nicole Philip, Laurence Faivre, Patrick Calvas, Karine Nguyen, Alice Masurel, Vidrica Ciorca, François Cartault, Jacqueline Vigneron, Alice Goldenberg, Jelena Martinovic, Monique Mozelle-Nivoix, Renaud Touraine, Ghislaine Plessis, Marie-Line Jacquemont, Jean-Luc Alessandri, Delphine Dupin-Deguine, Valérie Cormier-Daire, Aurélie Fabre, Jeanne Amiel, Marie Brechard, Bertrand Isidor, Salima El Chehadeh, Sylvie Odent, Isabelle Touitou, Josseline Kaplan, Dominique Martin-Coignard, Lucile Pinson, Sabine Sigaudy, Christine Coubes, Didier Lacombe, Frédéric Tm Them, 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de Hautepierre [Strasbourg], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHU La Réunion], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Biologie du Développement, Service de génétique médicale, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital l'Archet, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Toulouse], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut 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 ), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 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 clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Réanimation Néonatale et Pédiatrique, CHD Félix Guyon, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), 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 National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Service de Genetique, Service de Génétique Clinique, Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CH Le Mans, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), 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 ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), CHU Caen-Hôpital Clémenceau, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Hospices Civils de Lyon ( HCL ) -CHU de Lyon-Centre Neuroscience et Recherche, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), 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 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 de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: 0301 basic medicine, Proband, Male, Candidate gene, Hearing Loss, Sensorineural, [SDV]Life Sciences [q-bio], Biology, Osteochondrodysplasias, Article, 03 medical and health sciences, symbols.namesake, Kniest dysplasia, Protein Domains, Genetics, medicine, Humans, Connective Tissue Diseases, Collagen Type II, Genetics (clinical), Sanger sequencing, [ SDV ] Life Sciences [q-bio], Arthritis, Collagen Diseases, Retinal Detachment, medicine.disease, Phenotype, Human genetics, 3. Good health, Pedigree, 030104 developmental biology, Amino Acid Substitution, Dysplasia, Spondyloepiphyseal dysplasia congenita, symbols, Female
Abstract: International audience; Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.European Journal of Human Genetics advance online publication, 2 December 2015; doi:10.1038/ejhg.2015.250
Published: 2016
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31. Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

Author: Delphine Bonnet, Rosine Guimbaud, Pascaline Berthet, Anne-Françoise Cailleux, Marie-Pierre Buisine, Jacques Mauillon, Paul Gesta, David Malka, Stéphanie Baert-Desurmont, Estelle Cauchin, Estelle Houivet, Marine Lebrun, Caroline Abadie, Salima El Chehadeh, Isabelle Coupier, Lorena Ippolito, Julie Tinat, Philippe Jonveaux, Qing Wang, Marie Agnès Collonge-Rame, Françoise Desseigne, Sylvie Manouvrier, Jean-Christophe Saurin, Marion Gauthier-Villars, Jean-Marc Rey, Catherine Dugast, Laurence Brugières, Christine Toulas, Brigitte Bressac-de Paillerets, Pierre Laurent-Puig, Pascal Pujol, Sophie Giraud, Fabienne Prieur, Florence Polycarpe-Osaer, Jean Chiesa, Jacques Benichou, Dominique Leroux, Bruno Buecher, Ludovic Mansuy, Marie-Emmanuelle Morin-Meschin, Joanna Sokolowska, Marion Bougeard, Sophie Lejeune, Myriam Bronner, Jacqueline Duffour, Agnès Hardouin, Hakim Sebaoui, Valérie Bonadona, Julien Blot, Chrystelle Colas, Aziz Zaanan, Olivier Caron, Françoise Charbonnier, François Duhoux, Thierry Frebourg, Laurence Faivre, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Cancéropole Nord-Ouest, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), Oncologie thoracique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Institut Curie Paris, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique Clinique [CHRU Nïmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Onco-génétique, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de génétique [Cliniques Universitaires Saint-Luc, Bruxelles], Cliniques Universitaires Saint-Luc [Bruxelles], Génétique biologique histologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), 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), Service d'Hépatologie et de Gastroentérologie [Lyon], Unité de recherche clinique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU), and UL, NGERE
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Genotyping Techniques, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene Frequency, Risk Factors, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Prospective cohort study, Alleles, Genetics (clinical), Chromosomes, Human, Pair 15, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Lynch syndrome, 3. Good health, SNP genotyping, [SDV] Life Sciences [q-bio], 030104 developmental biology, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 18, Colorectal Neoplasms, business, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract: International audience; To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's chi(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P
Published: 2016
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32. Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome

Author: David Masson, Jamal Ghoumid, Elodie Gautier, Valérie Deckert, Laurent Lagrost, Virginie Carmignac, Nathalie Marle, Christel Thauvin-Robinet, Edward Blair, Laurence Faivre, Thomas Gautier, Gaëtan Jego, Jean-Michel Petit, Patrick Edery, Laurence Duplomb, Marie-Claude Brindisi, Floriane Limoge, Salima El Chehadeh-Djebbar, Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Université Bourgogne Franche-Comté ( UBFC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), FHU TRANSLAD, Département de Génétique, Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Nord, Centre Hospitalier Universitaire de Lille ( CHU de Lille ), Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, and the French Ministry of Health (PHRC 2012, A00103-42) and the Regional Council of Burgundy (STIC11).
Subjects: Male, obesity, medicine.medical_treatment, Developmental Disabilities, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Vesicular Transport Proteins, Adipose tissue, Myopia, Body Fat Distribution, Insulin, Child, ppar-gamma, Genetics (clinical), Retinal Degeneration, General Medicine, differentiation, Middle Aged, VPS13B, Child, Preschool, [ SCCO.NEUR ] Cognitive science/Neuroscience, Microcephaly, Muscle Hypotonia, Female, Signal Transduction, Adult, Risk, medicine.medical_specialty, alpha, Adolescent, Biology, Models, Biological, adipogenesis, Fingers, resistance, Young Adult, Insulin resistance, Internal medicine, Diabetes mellitus, Intellectual Disability, Genetics, medicine, Humans, definition, [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT], gene, Molecular Biology, Cohen syndrome, medicine.disease, Obesity, Endocrinology, Diabetes Mellitus, Type 2, Mutation, transport, Metabolic syndrome, protein
Abstract: Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus. Besides congenital neutropenia, retinopathy and intellectual deficiency, CS patients are faced with truncal obesity. Metabolism investigations showed abnormal glucose tolerance tests and low HDL values in some patients, and these could be risk factors for the development of diabetes mellitus and/or cardiovascular complications. To understand the mechanisms involved in CS fat storage, we used two models of adipogenesis differentiation: (i) SGBS pre-adipocytes with VPS13B invalidation thanks to siRNA delivery and (ii) CS primary fibroblasts. In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance. This study, in association with the in-depth analysis of the metabolic status of the patients, thus allowed us to recommend appropriate nutritional education to prevent the occurrence of diabetes mellitus and to put forward recommendations for the follow-up of CS patients, in particular with regard to the development of metabolic syndrome. We also suggest replacing the term obesity by abnormal fat distribution in CS, which should reduce the number of inappropriate diagnoses in patients who are referred only on the basis of intellectual deficiency associated with obesity.
Published: 2015
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33. Infectious and Immunologic Phenotype of MECP2 Duplication Syndrome

Author: Thusari Gomes, Fabian Marc Kaiser, Salima El-Chehadeh, Horst von Bernuth, Bernard Echenne, Maria P. Botella, Karin Hameister, Rainer Rossi, Maria-Isabel Tejada, Volker Wahn, Sophie Julia, Christian Meisel, Nadine Unterwalder, Michael Bauer, Renate Krüger, Xiu Xu, Nicole Philip, Magdalena Budisteanu, Alexandra Afenjar, Dagmar Wieczorek, Hilde Van Esch, Sorina Mihaela Papuc, Ludwig Gortner, Francisco Martínez, Oliver Patat, Mónica Roselló, Uwe Kölsch, Renaud Touraine, Aleksandra Jezela-Stanek, Kirsten Wenner, Annick Toutain, Carmen Orellana, and Aglaia Vignoli
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Genotype, Methyl-CpG-Binding Protein 2, Immunology, MECP2 duplication syndrome, Medizin, Immunoglobulins, Biology, Infections, primary immunodeficiency, Sepsis, Cohort Studies, Young Adult, methyl CpG binding protein 2 (MECP2), Medical microbiology, Gene Duplication, Gene duplication, medicine, Immunology and Allergy, Humans, Child, Immunodeficiency, Original Research, Immunity, Cellular, Antibody titer, Middle Aged, medicine.disease, Immunity, Humoral, Pneumonia, C-Reactive Protein, Phenotype, intellectual disability, Child, Preschool, Primary immunodeficiency, Mental Retardation, X-Linked, Female, Xq28-duplication syndrome, humoral immunodeficiency, Acute-Phase Proteins
Abstract: MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG2-deficiency was detected – in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG1-levels were detected in 11/21 patients and supra-normal IgG3-levels were seen in 8/21 patients – in 6 of the patients as combined elevation of IgG1 and IgG3. Three of the four patients with IgA/IgG2-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG2 may benefit from prophylactic substitution of sIgA and IgG. Electronic supplementary material The online version of this article (doi:10.1007/s10875-015-0129-5) contains supplementary material, which is available to authorized users.
Published: 2015

34. Large national series of patients with Xq28 duplication involving MECP2: Delineation of brain MRI abnormalities in 30 affected patients

Author: Vincent des Portes, Salima El Chehadeh, Odile Boespflug-Tanguy, Nathalie Marle, Charles Coutton, Didier Lacombe, Patrick Callier, Anne Moncla, Mathilde Nizon, Christine Francannet, Marlène Rio, Valérie Cormier-Daire, Jean-Paul Bonnefont, Pierre-Simon Jouk, Anne-Laure Mosca-Boidron, Christophe Philippe, Alice Goldenberg, Hubert Journel, Mathilde Lefebvre, Bertrand Isidor, Bernard Echenne, Séverine Drunat, Françoise Devillard, Sébastien Lebon, Jeanne Amiel, Nicole Philip, Jean-Marie Cuisset, Nathalie Perreton, Marie-Claude Addor, Fabienne Prieur, Christel Thauvin-Robinet, Laurent Pasquier, Sophie Julia, Christèle Dubourg, Danièle Martinet, Laurent Guibaud, Laetitia Lambert, Jeanne Andrieux, Cédric Le Caignec, Catherine Badens, Catherine Sarret, Alice Masurel, Julien Thevenon, Renaud Touraine, Ghislaine Plessis, Fanny Laffargue, Lydie Burglen, Laurence Perrin, Bruno Leheup, Thierry Bienvenu, Valérie Malan, Alexandra Afenjar, Albert David, Clarisse Baumann, Marie-Ange Delrue, Jacqueline Vigneron, Annick Toutain, Laurence Faivre, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, 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), Laboratoire de cytogénétique (CHU de Dijon), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, CHU Saint-Etienne, 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], Service de biologie moléculaire, Hôpital Pontchaillou, 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), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de neuropédiatrie [Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Department of pediatrics, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique médicale, 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 Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Département Génétique Médicale-Maternité, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Département de Génétique Médicale, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), 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]), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, 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]), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Génétique Médicale et Génomique Fonctionnelle (GMGF), 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 National de la Recherche Scientifique (CNRS), 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, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Référence ' Anomalies du Développement et Syndromes Malformatifs Sud - Est PACA ', Centre de référence maladie rare Thalassémie, CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Regional Council of Burgundy (PARI 2012), Association Xtraordinaire, Jonchère, Laurent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), 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), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Génétique, reproduction et développement ( GReD ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR79-Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ), Department of Genetics and Cytogenetics, CHU Clermont-Ferrand-Hôpital d'Estaing, Service de Génétique Médical, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Promoting Research Oriented Towards Early Cns Therapies ( PROTECT ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Caen-Hôpital Clémenceau, Hôpital Bretonneau-CHRU Tours, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Unité Fonctionnelle de Génétique Clinique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Service de Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de Génétique et d'Embryologie Médicale, Service de neuropédiatrie et pathologie du développement, CHU Cochin [AP-HP], Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( 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 ) -Hôpital Couple-Enfant, AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Maladies Rares - Génétique et Métabolisme ( MRGM ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), 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 National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ), Service de Génétique [Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and 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 )
Subjects: 0301 basic medicine, Male, Pathology, Methyl-CpG-Binding Protein 2, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Corpus callosum, Lateral ventricles, 0302 clinical medicine, Gene Duplication, IKBKG, FLNA, Child, Genetics (clinical), Genetics, Brain Diseases, medicine.diagnostic_test, Middle Aged, Prognosis, Magnetic Resonance Imaging, Hypotonia, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Phenotype, Xq28 duplication, Child, Preschool, Female, medicine.symptom, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Biology, genotype-phenotype correlation, White matter, 03 medical and health sciences, Young Adult, medicine, Humans, Genetic Association Studies, Chromosomes, Human, X, [ SDV ] Life Sciences [q-bio], Infant, Newborn, Infant, Magnetic resonance imaging, Hyperintensity, nervous system diseases, Mental Retardation, X-Linked, MECP2 gene, 030217 neurology & neurosurgery
Abstract: International audience; Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between \textgreater+2SD in five patients and \textless-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment. © 2015 Wiley Periodicals, Inc
Published: 2014
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35. 3q27.3 microdeletional syndrome: a recognisable clinical entity associating dysmorphic features, marfanoid habitus, intellectual disability and psychosis with mood disorder

Author: Hélène Poquet, Iben Bache, Bruno Vergès, Patrick Callier, Maria Luigia Cavaliere, Stanislas Lyonnet, Jean Paul Girod, Alice Masurel-Paulet, Valérie Malan, Anne Laure Mosca-Boidron, Nathalie Marle, Laurence Faivre, Antonio Novelli, Björn Menten, Julien Thevenon, Bart Loeys, Christel Thauvin-Robinet, Salima El Chehadeh, Frédéric Huet, Zeynep Tümer, Jean-Michel Petit, Jean Michel Pinoit, and Francine Mugneret
Subjects: Adult, Male, Psychosis, Candidate gene, Pediatrics, medicine.medical_specialty, Adolescent, Locus (genetics), Arachnodactyly, Young Adult, Intellectual Disability, Intellectual disability, Genetics, Medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Comparative Genomic Hybridization, business.industry, Mood Disorders, Marfanoid, Chromosome Mapping, Facies, Infant, Syndrome, medicine.disease, Phenotype, Mood disorders, Child, Preschool, Bone maturation, Female, Human medicine, Chromosomes, Human, Pair 3, Chromosome Deletion, business
Abstract: Background Since the advent of array-CGH, numerous new microdeletional syndromes have been delineated while others remain to be described. Although 3q29 subtelomeric deletion is a well-described syndrome, there is no report on 3q interstitial deletions. Methods We report for the first time seven patients with interstitial deletions at the 3q27.3q28 locus gathered through the Decipher database, and suggest this locus as a new microdeletional syndrome. Results The patients shared a recognisable facial dysmorphism and marfanoid habitus, associated with psychosis and mild to severe intellectual disability (ID). Most of the patients had no delay in gross psychomotor acquisition, but had severe impaired communicative and adaptive skills. Two small regions of overlap were defined. The first one, located on the 3q27.3 locus and common to all patients, was associated with psychotic troubles and mood disorders as well as recognisable facial dysmorphism. This region comprised several candidate genes including SST, considered a candidate for the neuropsychiatric findings because of its implication in interneuronal migration and differentiation processes. A familial case with a smaller deletion allowed us to define a second region of overlap at the 3q27.3q28 locus for marfanoid habitus and severe ID. Indeed, the common morphological findings in the first four patients included skeletal features from the marfanoid spectrum: scoliosis (4/4), long and thin habitus with leanness (average Body Mass Index of 15 (18.5
Published: 2013

36. Further delineation of eye manifestations in homozygous 15q13.3 microdeletions including TRPM1: a differential diagnosis of ceroid lipofuscinosis

Author: Patrick Callier, Salima El Chehadeh, Laurence Faivre, Alice Masurel-Paulet, Frédéric Huet, Isabelle Drumare, Christel Thauvin, Joris Andrieux, Louis Vallée, Jean-Christophe Cuvellier, Julien Thevenon, Philippe Pernes, Jean-Marie Cuisset, Muriel Holder, Sabine Defoort, and Béatrice Bourgois
Subjects: Male, Pathology, medicine.medical_specialty, genetic structures, alpha7 Nicotinic Acetylcholine Receptor, Encephalopathy, TRPM Cation Channels, Chromosome Disorders, Biology, Blindness, Eye, Pupil, Neuronal Ceroid-Lipofuscinoses, Night Blindness, Seizures, Intellectual Disability, Retinal Dystrophies, Genetics, medicine, Electroretinography, Myopia, Humans, Eye Abnormalities, Child, Genetics (clinical), TRPM1, Genetic Association Studies, Congenital stationary night blindness, Chromosomes, Human, Pair 15, Dystrophy, Eye Diseases, Hereditary, Genetic Diseases, X-Linked, Optic Nerve, Microdeletion syndrome, medicine.disease, Penetrance, Child, Preschool, Female, sense organs, Differential diagnosis, Chromosome Deletion
Abstract: The 15q13.3 heterozygous microdeletion is a fairly common microdeletion syndrome with marked clinical variability and incomplete penetrance. The average size of the deletion, which comprises six genes including CHRNA7, is 1.5 Mb. CHRNA7 has been identified as the gene responsible for the neurological phenotype in this microdeletion syndrome. Only seven patients with a homozygous microdeletion that includes at least CHRNA7, and is inherited from both parents have been described in the literature. The aim of this study was to further describe the distinctive eye manifestations from the analysis in the three French patients diagnosed with the classical 1.5 Mb homozygous microdeletion. Patients' ages ranged from 30 months to 9 years, and included one sib pair. They all displayed a remarkably severe identifiable clinical phenotype that included congenital blindness and convulsive encephalopathy with inconstant abnormal movements. The ophthalmological examination revealed a lack of eye tracking, optic nerve pallor, an immature response with increased latencies with no response to the checkerboard stimulations at the visual evoked potential examination, and a distinctive retina dystrophy with a negative electroretinogram in which the “b” wave was smaller than the “a” wave after a dark adapted pupil and bright flash in all patients. Clear genotype–phenotype correlations emerged, showing that this eye phenotype was secondary to homozygous deletion of TRPM1, the gene responsible for autosomal recessive congenital stationary night blindness. The main differential diagnosis is ceroid lipofuscinosis. © 2014 Wiley Periodicals, Inc.
Published: 2013

37. An improved method to extract DNA from 1 ml of uncultured amniotic fluid from patients at less than 16 weeks' gestation

Author: Julien Thevenon, C. Thauvin-Robinet, Anne-Laure Mosca-Boidron, Frédéric Huet, Laurence Faivre, Thierry Rousseau, Patrick Callier, Muriel Payet, Paul Sagot, Clémence Ragon, Serge Aho, Nathalie Marle, Salima El Chehadeh, Caroline Truntzer, and Francine Mugneret
Subjects: Adult, Pathology, medicine.medical_specialty, Amniotic fluid, lcsh:Medicine, Aneuploidy, Prenatal diagnosis, Gestational Age, Biology, Sensitivity and Specificity, Andrology, Cytogenetics, Chromosomal Disorders, Pregnancy, Diagnostic Medicine, Prenatal Diagnosis, medicine, Genetics, Humans, lcsh:Science, Pregnancy Trimesters, Chromosome Aberrations, Clinical Genetics, Comparative Genomic Hybridization, Multidisciplinary, lcsh:R, Gestational age, Obstetrics and Gynecology, Human Genetics, DNA, medicine.disease, Amniotic Fluid, DNA extraction, Cytogenetic Analysis, Gestation, Medicine, lcsh:Q, Female, Cytogenetic Techniques, Comparative genomic hybridization, Research Article, Test Evaluation
Abstract: The aim of this study was to develop an improved technique for DNA extraction from 1 ml of uncultured AF from patients with a gestational age less than 16 weeks and to allow the use of array-CGH without DNA amplification. The DNA extraction protocol was tested in a series of 90 samples including 41 of uncultured AF at less than 16 weeks of gestation. Statistical analyses were performed using linear regression. To evaluate the sensitivity and the specificity of array-CGH on 1 ml of uncultured AF, five samples with an abnormal karyotype (three with aneuploidy, two with structural abnormalities) and five with a normal karyotype were studied. This protocol was reproducible and we were able to show a great improvement with higher yield of DNA obtained from all patients, including those with a gestational age less than 16 weeks (p = 0.003). All chromosomal abnormalities were detected and characterized by array-CGH and normal samples showed normal profiles. This new DNA extraction protocol associated with array-CGH analysis could be used in prenatal testing even when gestational age is less than 16 weeks, especially in cases with abnormal ultrasound findings.
Published: 2012

38. The power of high-resolution non-targeted array-CGH in identifying intragenic rearrangements responsible for Cohen syndrome

Author: Anne-Laure Mosca-Boidron, Laurence Faivre, Veronica Cusin, Nadège Gigot, Salima El Chehadeh-Djebbar, Clémence Ragon, Frédéric Huet, Anne Moncla, Muriel Payet, Cornel Popovici, Anthonie J. van Essen, Bernard Aral, Christel Thauvin-Robinet, Alice Masurel-Paulet, Lucie Gueneau, Patrick Rump, Francine Mugneret, Patrick Callier, Nathalie Marle, Chantal Missirian, Jean-Raymond Teyssier, Irina Balikova, and Anne-Marie Frances
Subjects: Male, Genetics, Mutation, Cohen syndrome, Non targeted, DIAGNOSTIC-CRITERIA, Vesicular Transport Proteins, Biology, medicine.disease_cause, Bioinformatics, Compound heterozygosity, medicine.disease, Genome, GENE, VPS13B, DELINEATION, DELETIONS, Phenotype, medicine, Humans, Female, Allele, Gene, Genetics (clinical)
Abstract: We read with interest the article by Rivera-Brugues et al 1 in a recent issue of this journal describing 3 patients out of 1523 patients with unexplained mental retardation. Analysis by whole genome array-CGH (comparative genomic hybridisation) showed an intragenic heterozygous deletion in the VPS13B gene, and the subsequent sequencing of the VPS13B gene revealed by one-point mutation in the second allele in all three patients. In a previous study, we screened the VPS13B gene in 34 patients (28 families) with a suspicion of Cohen syndrome and identified 14 different mutations in 8 families (12 patients).2 The mutations were found in a compound heterozygous state in five families and in a homozygous state in one consanguineous family. In two other families (patients P1-F1, P2-F2 and P3-F2), only one heterozygous mutation was found (25% of families). Since the previous publication, 20 additional patients were screened, leading to the identification of compound heterozygosity in one patient and only one mutational event in four patients from three different families. All the patients with one or two mutational events in VPS13B were considered as having Cohen syndrome according to both Chandler's and Kolehmainen's criteria.3 4 Since the 244K array-CGH Agilent comprises 102 probes within the VPS13B gene (figure 1), we sought to identify a large intragenic event in two groups: group 1 included the five families in which one mutational event …
Published: 2011
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39. Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

Author: Emmanuel Raffo, Mathilde Lefebvre, Agathe Roubertie, Mondher Chouchane, Yannis Duffourd, Nathalie Villeneuve, Sandra Wahlen, Arnaud Lafon, Gaetan Lesca, Anne de Saint Martin, Delphine Héron, Laurent Villard, Cyril Mignot, Mathieu Milh, Alice Masurel-Paulet, Sylvie Odent, Laurence Faivre, Salima El Chehadeh, Annick Toutain, Julien Thevenon, Christel Thauvin-Robinet, Frédéric Huet, Bertrand Isidor, Clara Jugé, Jean-Baptiste Rivière, Christophe Philippe, Judith St-Onge, Damien Sanlaville, Véronique Darmency-Stamboul, François Feillet, Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Epilepsie et ischémie cérébrale, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de référence des maladies héréditaires du métabolisme ( MaMEA Nancy-Brabois ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de Médecine Infantile I [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité. ( DevAH ), Université de Lorraine ( UL ), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de Cytogénétique ( HFME ), Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service de génétique [Tours], Hôpital Bretonneau-CHRU Tours, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de pédiatrie (CHU de Dijon), Université de Technologie de Compiègne [Compiègne] ( UTC ), Service d'odontologie, médecine bucco-dentaire, chirurgie orale, implantologie (CHU de Dijon), Pôle de pédiatrie [CHU de Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg ( CHU de Strasbourg ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), 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 National de la Recherche Scientifique ( CNRS ), Unité de génétique médicale, Hôpital Sud, Service de Génétique [CHRU Nancy], Villard, Laurent, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité (DevAH), Université de Lorraine (UL), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Cytogénétique (HFME), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université de Technologie de Compiègne (UTC), Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Génétique Médicale et Génomique Fonctionnelle (GMGF), 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 National de la Recherche Scientifique (CNRS), hôpital Sud, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, [SDV]Life Sciences [q-bio], Genes, Recessive, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Compound heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Seizures, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Report, medicine, Genetics, Recessive, Humans, Ictal, Genetics(clinical), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetics (clinical), Exome sequencing, 030304 developmental biology, Subclinical infection, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Brain Diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [ SDV ] Life Sciences [q-bio], Symporters, Genetic heterogeneity, Citrate transport, medicine.disease, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], Genes, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.
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