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23 results on '"Service de génétique [Reims]"'

1. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Author

Aidin Foroutan, Sadegheh Haghshenas, Pratibha Bhai, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Marcello Niceta, Andrea Ciolfi, Lucia Pedace, Evelina Miele, David Genevieve, Solveig Heide, Mariëlle Alders, Giuseppe Zampino, Giuseppe Merla, Mélanie Fradin, Eric Bieth, Dominique Bonneau, Klaus Dieterich, Patricia Fergelot, Elise Schaefer, Laurence Faivre, Antonio Vitobello, Silvia Maitz, Rita Fischetto, Cristina Gervasini, Maria Piccione, Ingrid van de Laar, Marco Tartaglia, Bekim Sadikovic, Anne-Sophie Lebre, Foroutan A., Haghshenas S., Bhai P., Levy M.A., Kerkhof J., McConkey H., Niceta M., Ciolfi A., Pedace L., Miele E., Genevieve D., Heide S., Alders M., Zampino G., Merla G., Fradin M., Bieth E., Bonneau D., Dieterich K., Fergelot P., Schaefer E., Faivre L., Vitobello A., Maitz S., Fischetto R., Gervasini C., Piccione M., van de Laar I., Tartaglia M., Sadikovic B., Lebre A.-S., Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, University of Western Ontario (UWO), London Health Sciences Center (LHSC), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], 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 Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Amsterdam UMC - Amsterdam University Medical Center, University of Amsterdam [Amsterdam] (UvA), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University of Naples Federico II = Università degli studi di Napoli Federico II, Fondazione Casa Sollievo della Sofferenza [San Giovanni Rotondo, Italy] (FC2S), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, 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), 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), 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), 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), Les Hôpitaux Universitaires de Strasbourg (HUS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), San Gerardo Hospital [Monza, Italy] (SGH), Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Università degli Studi di Milano = University of Milan (UNIMI), Università degli studi di Palermo - University of Palermo, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Foroutan, A., Haghshenas, S., Bhai, P., Levy, M. A., Kerkhof, J., Mcconkey, H., Niceta, M., Ciolfi, A., Pedace, L., Miele, E., Genevieve, D., Heide, S., Alders, M., Zampino, G., Merla, G., Fradin, M., Bieth, E., Bonneau, D., Dieterich, K., Fergelot, P., Schaefer, E., Faivre, L., Vitobello, A., Maitz, S., Fischetto, R., Gervasini, C., Piccione, M., van de Laar, I., Tartaglia, M., Sadikovic, B., Lebre, A. -S., Martinez Rico, Clara, and Clinical Genetics

Subjects
Wiedemann–Steiner syndrome, QH301-705.5, Intellectual disability, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Catalysis, Inorganic Chemistry, KMT2A gene, Neurodevelopmental disorder, Growth Disorder, Abnormalities, Multiple, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biology (General), Physical and Theoretical Chemistry, Episignature, QD1-999, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Spectroscopy, DNA methylation, Organic Chemistry, Neurodevelopmental disorders, Craniofacial Abnormalitie, Epigenetic, Hypertrichosi, General Medicine, Facie, Computer Science Applications, Chemistry, epigenetics, episignature, intellectual disability, neurodevelopmental disorders, Phenotype, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Epigenetics, Human
Abstract

Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.

Published
2022

2. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature

Author

Delphine Breuillard, Isabelle Marey, Claire Bar, Tayeb Sekhara, Candace T. Myers, Diane Doummar, Alice Poisson, Hervé Isnard, Nathalie Dorison, Gwenaël Le Guyader, Arnold Munnich, Alexandra Afenjar, Anne de Saint Martin, Jamel Chelly, Gaetan Lesca, Gaetano Terrone, Rima Nabbout, Jeremy L. Freeman, David Geneviève, Sophie Dupont, Cyril Mignot, Katherine B. Howell, Giulia Barcia, Melanie Jennesson, Patrick Berquin, Sylvie Odent, Boris Keren, Ingrid E. Scheffer, Renzo Guerrini, Emmanuel Scalais, Thierry Billette de Villemeur, Martino Montomoli, Agnès Guët, Pierre Meyer, Anca Nica, Anne-Sophie Lebre, Edor Kabashi, Carla Marini, Amy L Schneider, Marion Gérard, Salima El Chehadeh, Heather C Mefford, Lynette G. Sadleir, Imagine - Institut des maladies génétiques (IMAGINE - U1163), 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), American Memorial Hospital, Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Melbourne, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), A Meyer Children's Hospital, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), 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)-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), CHU Amiens-Picardie, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Hôpital de Hautepierre [Strasbourg], Hôpitaux Universitaires de Strasbourg, Hôpital Louis-Mourier, Colombes, France., Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Rothschild Foundation Hospital, Paris., University of Washington [Seattle], Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia., A.Meyer Children's Hospital, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), 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), Section of Pediatrics-Child Neurology Unit, Federico II University, 80131, Naples, Italy, Centre Hospitalier Interrégional Edith Cavell (CHIREC), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CLAD-Ouest, CHU Rennes, France., University of Otago [Dunedin, Nouvelle-Zélande], Pediatric Neurology & Neurogenetics Unit and Laboratories, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, Epilepsy Research Centre, The Florey Institute of Neurosciences and Mental Health, Heidelberg, Victoria, Australia., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], H2020 European Research Council, Health Research Council of New Zealand, Agence Nationale de la Recherche, Seventh Framework Programme, Fondation Bettencourt Schueller, European Research Council, Bar, C, Barcia, G, Jennesson, M, Le Guyader, G, Schneider, A, Mignot, C, Lesca, G, Breuillard, D, Montomoli, M, Keren, B, Doummar, D, de Villemeur, Tb, Afenjar, A, Marey, I, Gerard, M, Isnard, H, Poisson, A, Dupont, S, Berquin, P, Meyer, P, Genevieve, D, De Saint Martin, A, El Chehadeh, S, Chelly, J, Guët, A, Scalais, E, Dorison, N, Myers, Ct, Mefford, Hc, Howell, Kb, Marini, C, Freeman, Jl, Nica, A, Terrone, G, Sekhara, T, Lebre, A, Odent, S, Sadleir, Lg, Munnich, A, Guerrini, R, Scheffer, Ie, Kabashi, E, Nabbout, R, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [APHP], Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Armand Trousseau, Hôpital Armand Trousseau, Paris, France., Centre de Référence déficiences intellectuelles de causes rares, GH Pitie-Salpêtrière-Charles Foix, F-, 75013, Paris, France., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier de Luxembourg, C.H.I.R.E.C, Brussels, Belgium., 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 ), Children's Hospital A. Meyer-University of Florence (UNIFI), 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], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Naples Federico II = Università degli studi di Napoli Federico II, 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 ), Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Children's Hospital A. Meyer-Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], 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)-Service de Neurologie [CHU Pitié-Salpêtrière]

Subjects
Genotype, [SDV]Life Sciences [q-bio], Biology, Structure-Activity Relationship, 03 medical and health sciences, Epilepsy, Shab Potassium Channels, KCNB1, Intellectual disability, Genetic variation, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Allele, developmental and epileptic encephalopathy, Alleles, Genetic Association Studies, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, Genetic Variation, medicine.disease, Axon initial segment, Phenotype, Neurodevelopmental Disorders, epilepsy, potassium channel
Abstract

International audience; Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the alpha subunit of the delayed-rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.

Published
2020

3. DNA ligase IV deficiency: Immunoglobulin class deficiency depends on the genotype

Author

Martine Doco-Fenzy, Mustapha Elalloussi, Laura C. Collopy, Jean-Pierre de Villartay, Aomar Agadr, Thierry Leblanc, Pierre-François Souchon, Tom Vulliami, Bérénice Hervé, Rodolphe Dard, Stephanie Gorde, Rachid Abilkassem, Alain Verloes, Abel Babik, Séverine Drunat, Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Service de génétique [Poissy], CHI Poissy-Saint-Germain, Service d'hématologie pédiatrique - CHU Reims, Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Barts & The London School of Medicine and Dentistry [London, UK] (Blizard Institute), Queen Mary University of London (QMUL), Hôpital Robert Debré Paris, Hôpital Robert Debré, American Memorial Hospital (Hôpital des enfants) [Reims], Rabat Military Hospital, Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), and Université de Reims Champagne-Ardenne (URCA)

Subjects
0301 basic medicine, [SDV.GEN]Life Sciences [q-bio]/Genetics, Severe combined immunodeficiency, Microcephaly, business.industry, Immunology, LIG4 syndrome, LIG4, medicine.disease, Pancytopenia, Short stature, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Seckel syndrome, Pediatrics, Perinatology and Child Health, medicine, Immunology and Allergy, medicine.symptom, business, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Immunodeficiency
Abstract

DNA ligase IV (LIG4) deficiency (LIG4 syndrome, LS, OMIM 606593) is a very rare autosomal-recessive DNA-repair disorder first reported in 2001(1). In LS, genome instability results in a broad range of Onco-Hemato-Immunological disturbances, including progressive pancytopenia in childhood, and severe combined immunodeficiency (SCID) B-T-NK+ and malignancy; it is also associated with microcephalic developmental delay, short stature, and facial dysmorphism. Clinical presentation ranges in severity from rapidly fatal to mild hemato-immunological forms associated with microcephalic developmental delay. This article is protected by copyright. All rights reserved.

Published
2017

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

Author

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

Subjects
0303 health sciences, business.industry, Published Erratum, MEDLINE, medicine.disease, computer.software_genre, Spelling, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine, Artificial intelligence, business, Psychology, computer, 030217 neurology & neurosurgery, Genetics (clinical), Natural language processing, 030304 developmental biology
Abstract

International audience; The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019

5. A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH

Author

François Vialard, Eva Pipiras, Pascale Kleinfinger, Dominique Martin-Coignard, Marie Catty, Elisabeth Flori, Emilie Landais, Mylène Valduga, Marie-France Portnoï, Aline Receveur, Agnès Choiset, Ghislaine Plessis, Nathalie Le Meur, Audrey Basinko, Justine Besseau-Ayasse, James Lespinasse, Radu Harbuz, Céline Poirsier, Martine Doco-Fenzy, Pascaline Letard, Caroline Schluth-Bolard, Anne Bazin, Jérôme Toutain, Fabienne Prieur, Florence Amblard, Cédric Le Caignec, Tiffany Busa, Marie Christine de Blois, Melanie Jimenez, Patrick Callier, Chantal Missirian, Céline Pebrel-Richard, Paul Kuentz, Catherine Yardin, François Cartault, Hakima Lallaoui, Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), UVSQ - Département de maïeutique (UVSQ Maïeutique), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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), CHU Bordeaux [Bordeaux], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Laboratoire de cytogénétique et génétique moléculaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Service de génétique, Centre hospitalier Félix Guyon, Bellepierre, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), CHU Clermont-Ferrand, Service de Génétique et d'Embryologie Médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Service d'Histologie, cytologie, cytogénétique, biologie cellulaire [CHU Limoges], CHU Limoges, Activité Motrice et Adaptation PsychoPhysiologique (AMAPP), Université d'Orléans (UO), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Laboratoire Pasteur Cerba, Laboratoire de Cytogénétique, CHI Poissy-Saint-Germain, Service de gynécologie et obstétrique [CHI Poissy-Saint Germain], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Laboratoire CERBA [Saint Ouen l'Aumône], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Association des Cytogénéticiens de Langue Française, Gamètes, implantation, gestation (GIG), 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 Pasteur [Paris]-Laboratoire CERBA [Saint Ouen l'Aumône], Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy]

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, 22q11 Deletion Syndrome, Adolescent, [SDV]Life Sciences [q-bio], Population, Article, 03 medical and health sciences, Intellectual disability, Genetics, medicine, Humans, Genetic Testing, Child, education, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Genetics (clinical), Comparative Genomic Hybridization, Fetus, education.field_of_study, business.industry, Incidence (epidemiology), Infant, Newborn, Cytogenetics, Infant, Microdeletion syndrome, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, Cohort, Paternal Inheritance, Female, France, business, Comparative genomic hybridization
Abstract

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.

Published
2015

6. Social cognition in ADHD: Irony understanding and recursive theory of mind

Author

Stéphanie Caillies, Michel Abely, Jacques Motte, Christine Raynaud, Vincine Bertot, Cognition, Santé, Société (C2S), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Maison des Sciences Humaines de Champagne-Ardenne (MSH-URCA), Université de Reims Champagne-Ardenne (URCA), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Chimie Agro-Industrielle (CAI), Institut National de la Recherche Agronomique (INRA)-Ecole nationale supérieure des ingénieurs en arts chimiques et technologiques-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Laboratoire de Chimie Agro-Industrielle (LCA), and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Supérieure de Chimie de Toulouse

Subjects
Male, media_common.quotation_subject, Theory of Mind, [SHS.PSY]Humanities and Social Sciences/Psychology, behavioral disciplines and activities, [SHS]Humanities and Social Sciences, Developmental psychology, Executive Function, [SCCO]Cognitive science, Typically developing, Cognition, Social cognition, Theory of mind, Developmental and Educational Psychology, Humans, Child, Social Behavior, media_common, Pragmatics, Executive functions, Irony, Comprehension, Clinical Psychology, Social Perception, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Female, Psychology, Cognitive psychology, Executive dysfunction
Abstract

International audience; The main goal of the present study was to characterise the social cognition abilities of French children with ADHD, in terms of their understanding of people's recursive mental states and their irony comprehension. We hypothesised that these children have difficulty understanding second-order false beliefs and ironic remarks, owing to the executive dysfunction that is characteristic of ADHD. We therefore conducted an experiment in which children with ADHD and typically developing matched controls performed second-order false-belief and executive function tasks. They then listened to ironic stories and answered questions about the ironic comments and about the speakers' beliefs and attitudes. The groups differed significantly on second-order theory of mind, irony comprehension and executive functions, confirming that children with ADHD have impaired social cognition.

Published
2014

7. Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3

Author

Robert W. Taylor, Lise Mathieu, Carole Le Bachelier, Abdelhamid Slama, Jean Bastin, Anne-Sophie Lebre, Fatima Djouadi, Alexandra Lopes Costa, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Biochimie [AP-HP Hôpital Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Wellcome Trust Centre for Mitochondrial Research [Newcastle upon Tyne, UK] (Institute of Genetic Medicine), Newcastle University [Newcastle]-International Centre for Life, Djouadi, Fatima, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, SIRT3, [SDV]Life Sciences [q-bio], SOD2, Mitochondrial diseases, Mitochondrion, Pharmacology, Resveratrol, Biology, Biochemistry, Antioxidants, Superoxide dismutase, 03 medical and health sciences, chemistry.chemical_compound, Oxygen Consumption, Physiology (medical), Sirtuin 3, Stilbenes, Humans, Cells, Cultured, chemistry.chemical_classification, Reactive oxygen species, Electron Transport Complex I, Superoxide Dismutase, Key terms: Complex I deficiency, Estrogen Receptor alpha, Pharmacological therapy, Complex I deficiency, Fibroblasts, 3. Good health, Mitochondria, [SDV] Life Sciences [q-bio], 030104 developmental biology, chemistry, Gene Expression Regulation, Receptors, Estrogen, Oxidative stress, biology.protein, NAD+ kinase, Signal transduction, Reactive Oxygen Species, Signal Transduction
Abstract

International audience; The pathophysiological mechanisms underlying Complex I (CI) deficiencies are understood only partially which severely limits the treatment of this common, devastating, mitochondrial disorder. Recently, we have shown that resveratrol (RSV), a natural polyphenol, has beneficial effects on CI deficiency of nuclear origin. Here, we demonstrate that RSV is able to correct the biochemical defect in oxygen consumption in five of thirteen CI-deficient patient cell lines. Other beneficial effects of RSV include a decrease of total intracellular ROS and the up-regulation of the expression of mitochondrial superoxide dismutase (SOD2) protein, a key antioxidant defense enzyme. The molecular mechanisms leading to the up-regulation of SOD2 protein expression by RSV require the estrogen receptor (ER) and the estrogen-related receptor alpha (ERRα). Although RSV increases the level of SOD2 protein in patients' fibroblasts, the enzyme activity is not increased, in contrast to normal fibroblasts. This led us to hypothesize that SOD2 enzyme activity is regulated post-translationally. This regulation involves SIRT3, a mitochondrial NAD þ-dependent deacetylase and is critically dependent on NAD þ levels. Taken together, our data show that the metabolic effects of RSV combined with its antioxidant capacities makes RSV particularly interesting as a candidate molecule for the therapy of CI deficiencies.

Published
2016

8. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients

Author

Marie-Ange Delrue, Nathalie Golovkine, Annick Toutain, Marie-Jose Gregoire, Christel Thauvin-Robinet, Nicolas Gruchy, Cédric Le Caignec, Emilie Landais, Bruno Delobel, Olivier Tassy, Pascal Sabouraud, Laurence Taine, Caroline Fiquet, Nathalie Leporrier, Agathe Paubel, Dominique Gaillard, Philippe Jonveaux, Nathalie Bednarek, Jacques Motte, Bruno Leheup, Olivier Brichet, Albert David, Didier Lacombe, Martine Doco-Fenzy, Stéphanie Arpin, Mylène Beri, Sylvain Briault, Monique Mozelle-Nivoix, Camille Leroy, Francine Mugneret, Service de Génétique, Centre Hospitalier Universitaire de Reims ( CHU Reims ) -Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne ( URCA ) -Université de Reims Champagne-Ardenne ( URCA ), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ), 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, Plateforme Régionale de Biologie Innovante, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Laboratoire de cytogénétique et génétique moléculaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Université de Lorraine ( UL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Maladies Rares - Génétique et Métabolisme ( MRGM ), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Service de génétique [Tours], Hôpital Bretonneau-CHRU Tours, Laboratoire de cytogénétique (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, American Memorial Hospital (Reims), Service de génétique [Reims], Service de psychothérapie de l’enfant et l’adolescent [CHU Reims], Université de Reims Champagne-Ardenne ( URCA ), Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Centre Hospitalier Universitaire de Reims (CHU Reims), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Maladies Rares - Génétique et Métabolisme (MRGM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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, Université de Reims Champagne-Ardenne (URCA), UL, NGERE, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Adult, Male, Candidate gene, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Chromosome Disorders, Locus (genetics), Biology, Fibrous Dysplasia, Polyostotic, Bioinformatics, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Humans, Child, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, KIF1A, Behavior, Comparative Genomic Hybridization, 0303 health sciences, [ SDV ] Life Sciences [q-bio], medicine.diagnostic_test, Brachydactyly, Chromosome Mapping, Overweight, Subtelomere, medicine.disease, [SDV] Life Sciences [q-bio], Child, Preschool, Chromosomes, Human, Pair 2, Autism, Female, Chromosome Deletion, 030217 neurology & neurosurgery, Comparative genomic hybridization, Fluorescence in situ hybridization
Abstract

International audience; The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable ‘2q37-deletion syndrome’ or Albright’s hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype–phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.

Published
2012

9. Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth

Author

Vera M. Kalscheuer, Céline Bonnet, Stefan A. Haas, Pierre Cacciagli, Sébastien Moutton, Emilie Landais, Laurent Villard, Jacques Motte, Ana Medeira, Martine Doco-Fenzy, Heng-Ye Man, Lionel Van Maldergem, Arjan P.M. de Brouwer, Marlène Rio, Christelle Cabrol, Juliette Dupont, Qingming Hou, Laurence Colleaux, Université Bourgogne Franche-Comté ( UBFC ), Boston University [Boston] ( BU ), Human Molecular Genetics, CHU Necker - Enfants Malades [AP-HP], 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, Centre Hospitalier Universitaire de Reims ( CHU Reims ) -Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne ( URCA ) -Université de Reims Champagne-Ardenne ( URCA ), Institute of Medical Genetics, Radboud University Medical Center [Nijmegen], Neuroscience Paris Seine ( NPS ), 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 ), Max Planck Institute for Molecular Genetics, 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 ), Service de Génétique Médicale du CHU de Bordeaux, Service de génétique [Reims], Centre Hospitalier Universitaire de Reims ( CHU Reims ), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Sciences Po Grenoble - Institut d'études politiques de Grenoble ( IEPG ), Regional Hospital, Boston University [Boston] (BU), Department Human Molecular Genetics [MPIMG Berlin], Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, 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 Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Department of Human Genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, American Memorial Hospital (Reims), and COLLEAUX, Laurence

Subjects
Male, Genetic Linkage, Bioinformatics, MESH: Child Development Disorders, Pervasive, 0302 clinical medicine, Genes, X-Linked, MESH: Child, Intellectual disability, MESH: Sequence Analysis, RNA, MESH: Animals, MESH: Genetic Variation, Child, Cells, Cultured, Genetics (clinical), X-linked recessive inheritance, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Massive parallel sequencing, Brain, Articles, General Medicine, Autism spectrum disorder, MESH: Young Adult, Child, Preschool, Gene Knockdown Techniques, MESH: Cells, Cultured, Adult, Adolescent, Neurite, MESH: Rats, MESH: Genetic Linkage, Context (language use), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Intellectual Disability, Young Adult, 03 medical and health sciences, MESH: Brain, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Neurites, medicine, Animals, Humans, Molecular Biology, Loss function, 030304 developmental biology, MESH: Adolescent, MESH: Humans, [ SDV ] Life Sciences [q-bio], Sequence Analysis, RNA, MESH: Child, Preschool, Genetic Variation, MESH: Adult, medicine.disease, MESH: Neurites, MESH: Gene Knockdown Techniques, MESH: Male, Rats, Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory [NCMLS 6], MESH: Genes, X-Linked, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child Development Disorders, Pervasive, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract

Item does not contain fulltext Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.

Published
2013

10. RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects

Author

Cécile, Jeanpierre, Guillaume, Macé, Mélanie, Parisot, Vincent, Morinière, Audrey, Pawtowsky, Marion, Benabou, Jelena, Martinovic, Jeanne, Amiel, Tania, Attié-Bitach, Anne-Lise, Delezoide, Philippe, Loget, Patricia, Blanchet, Dominique, Gaillard, Marie, Gonzales, Wassila, Carpentier, Patrick, Nitschke, Frédéric, Tores, Laurence, Heidet, Corinne, Antignac, Rémi, Salomon, J, Tantau, Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-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), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), CHU Necker - Enfants Malades [AP-HP], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], 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 biologie du développement[Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Service de génétique et de foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-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), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de bioinformatique, Université Paris Descartes - Paris 5 (UPD5), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte ( MARHEA ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Université de Reims Champagne-Ardenne ( URCA ) -IFR53-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Peer, Hal, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université

Subjects
medicine.medical_specialty, endocrine system, congenital, hereditary, and neonatal diseases and abnormalities, DNA Copy Number Variations, endocrine system diseases, 030232 urology & nephrology, Multicystic dysplastic kidney, Kidney development, medicine.disease_cause, Kidney, Polymorphism, Single Nucleotide, Congenital Abnormalities, 03 medical and health sciences, Open Reading Frames, 0302 clinical medicine, Fetus, renal agenesis, evolutionary conserved non-coding regions, Internal medicine, Genetics, medicine, Glial cell line-derived neurotrophic factor, Humans, Glial Cell Line-Derived Neurotrophic Factor, Multiple endocrine neoplasia, Renal agenesis, Genetics (clinical), Alleles, 030304 developmental biology, CNVs, 0303 health sciences, Mutation, variants, biology, Proto-Oncogene Proteins c-ret, Gene Expression Regulation, Developmental, medicine.disease, 3. Good health, Endocrinology, medicine.anatomical_structure, biology.protein, renal hypodysplasia, Kidney Diseases, Kidney disease, Signal Transduction
Abstract

International audience; Background The RET/GDNF signalling pathway plays a crucial role during development of kidneys and enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples. Objective and Methods To better characterize the involvement of RET and GDNF in kidney development defects, we studied a series of 105 fetuses with bilateral defects including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs and RET intron 1 were analysed. Copy number variations (CNVs) at these loci were also investigated. Results We identified: (i) a low frequency (< 7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (ii) no GDNF mutation; (iii) similar allele frequencies in patients and controls for most SNP variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs. 2%, P=0.01); (iv) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (v) absence of CNVs. Conclusion These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.

Published
2011

11. Monoallelic Loss-of-Function IFT140 Pathogenic Variants Cause Autosomal Dominant Polycystic Kidney Disease: A Confirmatory Study With Suspicion of an Additional Cardiac Phenotype.

Author

Salhi S, Doreille A, Dancer MS, Boueilh A, Filipozzi P, El Karoui K, Ponce F, Lebre AS, Raymond L, and Mesnard L

Subjects
Adolescent, Adult, Child, Female, Humans, Male, Alleles, Cardiomyopathy, Dilated genetics, Frameshift Mutation, Pedigree, Phenotype, Carrier Proteins genetics, Loss of Function Mutation, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant diagnosis
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. While biallelic variants affecting IFT140 are responsible for Mainzer-Saldino syndrome (characterized by severe ciliopathy causing skeletal abnormalities, kidney disease, and cysts), monoallelic loss-of-function (LoF) variants have been recently reported as an important cause of ADPKD beyond PKD1/2 genes. Herein, we report 6 non-family-related cases of monoallelic IFT140 LoF variants, identified from 1,340 exomes sequenced for nephrological indications in our local database. Every patient presented with polycystic kidney disease. Furthermore, the mother of a boy diagnosed with Mainzer-Saldino syndrome with a biallelic variant affecting IFT140 presented with several bilateral cysts, revealed after kidney imaging, and was found to carry a pathologic frameshift IFT140 variation. As well as this particular Mainzer-Saldino case, our 6 additional patients confirm that heterozygous IFT140 frameshift variants are responsible for the cystic phenotype and kidney failure. Interestingly, of the 6 patients, 2 also exhibited dilated cardiomyopathy, which was of unknown origin, as no genetic cause was found after exome sequencing analysis, suggesting a potential connection between IFT140 and heart disease., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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12. Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.

Author

Nicolas G, Zaréa A, Lacour M, Quenez O, Rousseau S, Richard AC, Bonnevalle A, Schramm C, Olaso R, Sandron F, Boland A, Deleuze JF, Andriuta D, Anthony P, Auriacombe S, Balageas AC, Ballan G, Barbay M, Béjot Y, Belliard S, Benaiteau M, Bennys K, Bombois S, Boutoleau-Bretonnière C, Branger P, Carlier J, Cartz-Piver L, Cassagnaud P, Ceccaldi MP, Chauviré V, Chen Y, Cogez J, Cognat E, Contegal-Callier F, Corneille L, Couratier P, Cretin B, Crinquette C, Dauriat B, Dautricourt S, de la Sayette V, de Liège A, Deffond D, Demurger F, Deramecourt V, Derollez C, Dionet E, Doco Fenzy M, Dumurgier J, Dutray A, Etcharry-Bouyx F, Formaglio M, Gabelle A, Gainche-Salmon A, Godefroy O, Graber M, Gregoire C, Grimaldi S, Gueniat J, Gueriot C, Guillet-Pichon V, Haffen S, Hanta CR, Hardy C, Hautecloque G, Heitz C, Hourregue C, Jonveaux T, Jurici S, Koric L, Krolak-Salmon P, Lagarde J, Lanoiselée HM, Laurens B, Le Ber I, Le Guyader G, Leblanc A, Lebouvier T, Levy R, Lippi A, Mackowiak MA, Magnin E, Marelli C, Martinaud O, Maureille A, Migliaccio R, Milongo-Rigal E, Mohr S, Mollion H, Morin A, Nivelle J, Noiray C, Olivieri P, Paquet C, Pariente J, Pasquier F, Perron A, Philippi N, Planche V, Pouclet-Courtemanche H, Rafiq M, Rollin-Sillaire A, Roué-Jagot C, Saracino D, Sarazin M, Sauvée M, Sellal F, Teichmann M, Thauvin C, Thomas Q, Tisserand C, Turpinat C, Van Damme L, Vercruysse O, Villain N, Wagemann N, Charbonnier C, and Wallon D

Subjects
Humans, Female, Male, Aged, Risk Factors, Prospective Studies, Middle Aged, Presenilin-1 genetics, Pedigree, Age of Onset, Amyloid beta-Protein Precursor genetics, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease diagnosis, Genetic Testing methods, Genetic Predisposition to Disease, Exome Sequencing, Presenilin-2 genetics, Membrane Glycoproteins, Receptors, Immunologic
Abstract

Purpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD)., Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92)., Results: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees., Conclusion: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure., Competing Interests: Conflict of Interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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13. Lessons from two series by physicians and caregivers' self-reported data in DDX3X-related disorders.

Author

Ruault V, Burger P, Gradels-Hauguel J, Ruiz N, Jamra RA, Afenjar A, Alembik Y, Alessandri JL, Arpin S, Barcia G, Bendová Š, Bruel AL, Charles P, Chatron N, Chopra M, Conrad S, Daire VC, Cospain A, Coubes C, Coursimault J, Delahaye-Duriez A, Doco M, Dufour W, Durand B, Engel C, Faivre L, Ferroul F, Fradin M, Frenkiel H, Fusco C, Garavelli L, Garde A, Gerard B, Germanaud D, Goujon L, Gouronc A, Ginglinger E, Goldenberg A, Hancarova M, Havlovicová M, Heron D, Isidor B, Marçais NJ, Keren B, Koch-Hogrebe M, Kuentz P, Lamure V, Lebre AS, Lecoquierre F, Lehman N, Lesca G, Lyonnet S, Martin D, Mignot C, Neuhann TM, Nicolas G, Nizon M, Petit F, Philippe C, Piton A, Pollazzon M, Prchalová D, Putoux A, Rio M, Rondeau S, Rossi M, Sabbagh Q, Saugier-Veber P, Schmetz A, Steffann J, Thauvin-Robinet C, Toutain A, Them FTM, Trimarchi G, Vincent M, Vlčková M, Wieczorek D, Willems M, Yauy K, Zelinová M, Ziegler A, Chaumette B, Sadikovic B, Mandel JL, and Geneviève D

Subjects
Child, Preschool, Humans, DEAD-box RNA Helicases, Self Report, Infant, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity therapy, Caregivers
Abstract

Introduction and Methods: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers., Results: These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words., Discussion: Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Published
2024
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14. BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.

Author

Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, and Piard J

Subjects
Humans, Nuclear Proteins genetics, Phenotype, Genotype, Genetic Association Studies, Atrophy, Epilepsy genetics, Neurodegenerative Diseases genetics
Abstract

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17)., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Published
2023
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15. Mutational Characteristics of Primary Mucosal Melanoma: A Systematic Review.

Author

Beaudoux O, Oudart JB, Riffaud L, Visseaux L, Marchal A, Lebre AS, and Grange F

Subjects
Humans, Membrane Glycoproteins genetics, Mutation, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-kit genetics, TOR Serine-Threonine Kinases genetics, Melanoma pathology, Skin Neoplasms genetics
Abstract

Background: Primary mucosal melanomas (PMMs) are rare and clinically heterogeneous, including head and neck (HNMs), vulvovaginal (VVMs), conjunctival (CjMs), anorectal (ARMs) and penile (PMs) melanomas. While the prognosis of advanced cutaneous melanoma has noticeably improved using treatments with immune checkpoint inhibitors (ICIs) and molecules targeting BRAF and MEK, few advances have been made for PMMs because of their poorer response to ICIs and their different genetic profile. This prompted us to conduct a systematic review of molecular studies of PMMs to clarify their pathogenesis and potential therapeutic targets., Methods: All articles that examined gene mutations in PMMs were identified from the databases and selected based on predefined inclusion criteria. Mutation rate was calculated for all PMMs and each location group by relating the number of mutations identified to the total number of samples analysed., Results: Among 1,581 studies identified, 88 were selected. Overall, the frequency of KIT, BRAF and NRAS mutation was 13.5%, 12.9% and 12.1%, respectively. KIT mutation ranged from 6.4% for CjMs to 16.6% for ARMs, BRAF mutation from 8.6% for ARMs to 31.1% for CjMs, and NRAS mutation from 6.2% for ARMs to 18.5% for CjMs. Among 101 other genes analysed, 33 had mutation rates over 10%, including TTN, TSC1, POM121, NF1, MTOR and SF3B1., Conclusion: In addition to BRAF, NRAS and KIT genes commonly studied, our systematic review identified significantly mutated genes that have already been associated (e.g., TSC1, mTOR, POLE or ATRX) or could be associated with (future) targeted therapies., Prospero Id: CRD42020185552., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Published
2022
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16. Nephronophthisis in Young Adults Phenocopying Thrombotic Microangiopathy and Severe Nephrosclerosis.

Author

Doreille A, Raymond L, Lebre AS, Linster C, Saraeva Lamri R, Karras A, Khayat R, Michel PA, Buob D, Luque Y, Rafat C, and Mesnard L

Subjects
Adult, Female, Humans, Kidney Diseases, Cystic genetics, Male, Severity of Illness Index, Young Adult, Kidney Diseases, Cystic congenital, Nephrosclerosis genetics, Phenotype, Thrombotic Microangiopathies genetics
Published
2021
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17. Adult diagnosis of Townes-Brocks syndrome with renal failure: Two related cases and review of literature.

Author

Beaudoux O, Lebre AS, Doco Fenzy M, Spodenkiewicz M, Canivet E, Colosio C, and Poirsier C

Subjects
Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Abortion, Habitual genetics, Anus, Imperforate diagnosis, Anus, Imperforate genetics, Delayed Diagnosis, Ear, External abnormalities, Female, Hammer Toe Syndrome genetics, Hearing Loss, Bilateral genetics, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural genetics, Humans, Kidney Failure, Chronic surgery, Kidney Failure, Chronic therapy, Kidney Transplantation, Middle Aged, Pedigree, Peripheral Nervous System Diseases genetics, Phenotype, Polydactyly genetics, Renal Dialysis, Retinal Dystrophies genetics, Anus, Imperforate complications, Hearing Loss, Sensorineural complications, Kidney Failure, Chronic etiology, Thumb abnormalities, Transcription Factors genetics
Abstract

Townes-Brocks syndrome (TBS) is a rare autosomal dominant syndrome, resulting from heterozygous variant in SALL1 gene and initially characterized by the triad of anorectal, thumb, and ear malformations. Essentially described in children, adult case reports are uncommon. Renal involvement has already been reported in adults and children but poorly described. Structural abnormalities such as hypodysplasia, unilateral renal agenesis or multicystic kidneys have been described, as well as functional impairment (with or without structural abnormalities) that may progress to end-stage renal disease (ESRD). We report two adult cases (mother and daughter) which exhibited kidney hypoplasia (focal and segmental glomerulosclerosis for the mother) and ESRD. The mother had unilateral polydactyly. TBS was suggested after physical examination. TBS diagnosis was confirmed by identification of a SALL1 variant. We conducted a literature review to evaluate the renal anomalies in TBS cases diagnosed in adulthood. Among 44 adult cases of TBS with genetic confirmation (including our two cases), 10 had kidney disease. The circumstances of renal failure diagnosis were incidental findings (2/5), gout (2/5), or repeated episodes of pyelonephritis (1/5). The median age of kidney disease diagnosis was 30 years old and of renal transplant 49 years old. The most frequent renal malformation was bilateral kidney hypoplasia. TBS is probably underestimated in adulthood and this report highlights that less obvious elements of morphology such as dysplasic ears can facilitate the diagnosis of TBS. As long-term prognosis of renal involvement in TBS patients remains largely unknown, a regular evaluation is required throughout life for patients., (© 2021 Wiley Periodicals LLC.)

Published
2021
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18. Prolidase deficiency: a new genetic cause of combined pulmonary fibrosis and emphysema syndrome in the adult.

Author

Cottin V, Nasser M, Traclet J, Chalabreysse L, Lèbre AS, Si-Mohamed S, Philit F, and Thivolet-Béjui F

Subjects
Adult, Humans, Emphysema, Prolidase Deficiency, Pulmonary Emphysema complications, Pulmonary Emphysema genetics, Pulmonary Fibrosis complications, Pulmonary Fibrosis genetics
Abstract

Competing Interests: Conflict of interest: V. Cottin has nothing to disclose. Conflict of interest: M. Nasser has nothing to disclose. Conflict of interest: J. Traclet has nothing to disclose. Conflict of interest: L. Chalabreysse has nothing to disclose. Conflict of interest: A-S. Lèbre has nothing to disclose. Conflict of interest: S. Si-Mohamed has nothing to disclose. Conflict of interest: F. Philit has nothing to disclose. Conflict of interest: F. Thivolet-Béjui has nothing to disclose.

Published
2020
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19. Correction: The landscape of epilepsy-related GATOR1 variants.

Author

Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, de Saint Martin A, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez-Hernandez L, Krithika S, Oegema R, Hagebeuk E, Gunning B, Deckers C, Berghuis B, Wegner I, Niks EH, Jansen FE, Braun K, de Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, NordliJr DR, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, de Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, and Baulac S

Abstract

The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019
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20. Correction to: The landscape of epilepsy-related GATOR1 variants.

Author

Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, Martin AS, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez-Hernandez L, Krithika S, Oegema R, Hagebeuk E, Gunning B, Deckers C, Berghuis B, Wegner I, Niks E, Jansen F, Braun K, Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, NordliJr DR, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, and Baulac S

Abstract

The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.

Published
2019
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21. eKLIPse: a sensitive tool for the detection and quantification of mitochondrial DNA deletions from next-generation sequencing data.

Author

Goudenège D, Bris C, Hoffmann V, Desquiret-Dumas V, Jardel C, Rucheton B, Bannwarth S, Paquis-Flucklinger V, Lebre AS, Colin E, Amati-Bonneau P, Bonneau D, Reynier P, Lenaers G, and Procaccio V

Subjects
Base Sequence genetics, Genetic Association Studies, High-Throughput Nucleotide Sequencing methods, Humans, Mitochondria genetics, Mitochondrial Diseases diagnosis, Software, DNA, Mitochondrial genetics, Sequence Analysis, DNA methods, Sequence Deletion genetics
Abstract

Purpose: Accurate detection of mitochondrial DNA (mtDNA) alterations is essential for the diagnosis of mitochondrial diseases. The development of high-throughput sequencing technologies has enhanced the detection sensitivity of mtDNA pathogenic variants, but the detection of mtDNA rearrangements, especially multiple deletions, is still poorly processed. Here, we present eKLIPse, a sensitive and specific tool allowing the detection and quantification of large mtDNA rearrangements from single and paired-end sequencing data., Methods: The methodology was first validated using a set of simulated data to assess the detection sensitivity and specificity, and second with a series of sequencing data from mitochondrial disease patients carrying either single or multiple deletions, related to pathogenic variants in nuclear genes involved in mtDNA maintenance., Results: eKLIPse provides the precise breakpoint positions and the cumulated percentage of mtDNA rearrangements at a given gene location with a detection sensitivity lower than 0.5% mutant. eKLIPse software is available either as a script to be integrated in a bioinformatics pipeline, or as user-friendly graphical interface to visualize the results through a Circos representation ( https://github.com/dooguypapua/eKLIPse )., Conclusion: Thus, eKLIPse represents a useful resource to study the causes and consequences of mtDNA rearrangements, for further genotype/phenotype correlations in mitochondrial disorders.

Published
2019
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22. The landscape of epilepsy-related GATOR1 variants.

Author

Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, de Saint Martin A, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez-Hernandez L, Krithika S, Oegema R, Hagebeuk E, Gunning B, Deckers C, Berghuis B, Wegner I, Niks E, Jansen FE, Braun K, de Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, Nordli DR Jr, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, de Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, and Baulac S

Subjects
Adolescent, Brugada Syndrome genetics, Brugada Syndrome mortality, Brugada Syndrome physiopathology, Child, Child, Preschool, DNA Copy Number Variations genetics, Epilepsy complications, Epilepsy epidemiology, Epilepsy physiopathology, Female, Genetic Predisposition to Disease, Humans, INDEL Mutation genetics, Infant, Infant, Newborn, Loss of Function Mutation genetics, Male, Mechanistic Target of Rapamycin Complex 1 genetics, Multiprotein Complexes genetics, Pedigree, Seizures complications, Seizures epidemiology, Seizures genetics, Seizures physiopathology, Signal Transduction genetics, Epilepsy genetics, GTPase-Activating Proteins genetics, Repressor Proteins genetics, Tumor Suppressor Proteins genetics
Abstract

Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants., Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign., Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Published
2019
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23. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.

Author

Leroy C, Landais E, Briault S, David A, Tassy O, Gruchy N, Delobel B, Grégoire MJ, Leheup B, Taine L, Lacombe D, Delrue MA, Toutain A, Paubel A, Mugneret F, Thauvin-Robinet C, Arpin S, Le Caignec C, Jonveaux P, Beri M, Leporrier N, Motte J, Fiquet C, Brichet O, Mozelle-Nivoix M, Sabouraud P, Golovkine N, Bednarek N, Gaillard D, and Doco-Fenzy M

Subjects
Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, Pair 2 genetics, Comparative Genomic Hybridization, DNA Copy Number Variations genetics, Female, Genetic Association Studies, Humans, Male, Young Adult, Behavior, Brachydactyly complications, Brachydactyly genetics, Chromosome Disorders complications, Chromosome Disorders genetics, Fibrous Dysplasia, Polyostotic complications, Fibrous Dysplasia, Polyostotic genetics, Intellectual Disability complications, Intellectual Disability genetics, Overweight complications, Overweight genetics
Abstract

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.

Published
2013
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