Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18373
Title: High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
Authors: Hamdan, Fadi F;Myers, Candace T;Cossette, Patrick;Lemay, Philippe;Spiegelman, Dan;Laporte, Alexandre Dionne;Nassif, Christina;Diallo, Ousmane;Monlong, Jean;Cadieux-Dion, Maxime;Dobrzeniecka, Sylvia;Riou, Emilie;Srour, Myriam;Carmant, Lionel;Lortie, Anne;Major, Philippe;Diadori, Paola;Dubeau, François;D'Anjou, Guy;Bourque, Guillaume;Berkovic, Samuel F;Sadleir, Lynette G;Campeau, Philippe M;Kibar, Zoha;Lafrenière, Ronald G;Girard, Simon L;Mercimek-Mahmutoglu, Saadet;Boelman, Cyrus;Rouleau, Guy A;Scheffer, Ingrid E;Mefford, Heather C;Andrade, Danielle M;Rossignol, Elsa;Minassian, Berge A;Michaud, Jacques L;Meloche, Caroline;Retterer, Kyle;Cho, Megan T;Rosenfeld, Jill A;Bi, Weimin;Massicotte, Christine;Miguet, Marguerite;Brunga, Ledia;Regan, Brigid M;Mo, Kelly;Tam, Cory;Schneider, Amy;Hollingsworth, Georgie;FitzPatrick, David R;Donaldson, Alan;Canham, Natalie;Blair, Edward;Kerr, Bronwyn;Fry, Andrew E;Thomas, Rhys H;Shelagh, Joss;Hurst, Jane A;Brittain, Helen;Blyth, Moira;Lebel, Robert Roger;Gerkes, Erica H;Davis-Keppen, Laura;Stein, Quinn;Chung, Wendy K;Dorison, Sara J;Benke, Paul J;Fassi, Emily;Corsten-Janssen, Nicole;Kamsteeg, Erik-Jan;Mau-Them, Frederic T;Bruel, Ange-Line;Verloes, Alain;Õunap, Katrin;Wojcik, Monica H;Albert, Dara V F;Venkateswaran, Sunita;Ware, Tyson;Jones, Dean;Liu, Yu-Chi;Mohammad, Shekeeb S;Bizargity, Peyman;Bacino, Carlos A;Leuzzi, Vincenzo;Martinelli, Simone;Dallapiccola, Bruno;Tartaglia, Marco;Blumkin, Lubov;Wierenga, Klaas J;Purcarin, Gabriela;O'Byrne, James J;Stockler, Sylvia;Lehman, Anna;Keren, Boris;Nougues, Marie-Christine;Mignot, Cyril;Auvin, Stéphane;Nava, Caroline;Hiatt, Susan M;Bebin, Martina;Shao, Yunru;Scaglia, Fernando;Lalani, Seema R;Frye, Richard E;Jarjour, Imad T;Jacques, Stéphanie;Boucher, Renee-Myriam
Affiliation: Program in Genetics and Genome Biology, Division of Neurology, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada
Division of Child Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX 75390, USA
Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA
Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada
Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO 64108, USA
Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO 64108, USA
GeneDx, Gaithersburg, MD 20877, USA
Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA
Division of Neurology, Epilepsy Genetics Program, Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
Clinical Genetics Service, University Hospitals Bristol NHS Foundation Trust, St. Michael's Hospital, St. Michael's Hill, Bristol BS2 8DT, UK
North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK
Oxford Centre for Genomic Medicine, ACE building Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK
MRC Centre for Neuropsychiatric Genetics & Genomics, Hadyn Ellis Building, Cathays, Cardiff University, Cardiff CF24 4HQ, UK
West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK
Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK
Department of Pediatrics, Section of Medical Genetics, SUNY Upstate Medical University, Syracuse, NY 13210, USA
University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands
University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57117, USA
Augustana-Sanford Genetic Counseling Graduate Program, Sioux Falls, SD 57197, USA
Departments of Medicine and Pediatrics, Columbia University Medical Center, New York, NY 10032, USA
Baptist Hospital, Miami, FL 33176 USA
Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Department of Human Genetics, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
Équipe INSERM 1231, Génétique des Anomalies du Développement, Université de Bourgogne, 21000 Dijon, France
Centre de Génétique des Anomalies du Développement, Centre Hospitalier Universitaire de Dijon, 21000 Dijon, France
Genetics Department, Assistance Publique - Hôpitaux de Paris, Robert-Debré University Hospital, 75000 Paris, France
Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu 51014, Estonia
Division of Genetics and Genomics and Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Nationwide Children's Hospital and Ohio State University, Department of Pediatrics, Division of Neurology, Columbus, OH 43205, USA
Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
University of Tasmania, Royal Hobart Hospital, Department of Paediatrics, Hobart, TAS 7000, Australia
School of Medicine, University of Tasmania, Hobart, TAS 7000, Australia
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Children's Hospital at Westmead Clinical School, University of Sydney, Westmead, NSW 2145, Australia
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Texas Children's Hospital, Houston, TX 77030, USA
Dipartimento di Pediatria e di Neuropsichiatria Infantile, Università La Sapienza, 00185 Rome, Italy
Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, 00161 Rome, Italy
Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy
Metabolic Neurogenetic Clinic and Pediatric Movement Disorders Clinic, Wolfson Medical Center, Holon 5822012, Israel
University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
University of British Columbia, BC Children's Hospital, Vancouver, BC V6H 3N1, Canada
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
Assistance Publique - Hôpitaux de Paris, Hôpital d'Enfants Armand Trousseau, Service de Neuropédiatrie, Paris 75012, France
Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR 1141, Paris 75019, France
Assistance Publique - Hôpitaux de Paris, Hôpital Robert Debré, Service de Neurologie Pédiatrique, Paris 75019, France
Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique "Déficiences Intellectuelles et Autisme," Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, Paris 75013, France
Sorbonne Universités, Université Pierre et Marie Curie (Université Paris 06), UMRS 1127, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Épinière, Paris 75013, France
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Arkansas Children's Research Institute, Little Rock, AR 72205, USA
Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA
Centre Hospitalier Rouyn-Noranda, Rouyn-Noranda, QC J9X 2B2, Canada
Division of Neurology, Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada
Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
Department of Pediatrics, McGill University, Montreal, QC H3A 1A4, Canada
Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A2B4, Canada
Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada
McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada
Department of Pediatrics and Child Health, University of Otago, Wellington 9016, New Zealand
Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada
Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Division of Neurology, BC Children's Hospital, Vancouver, BC V6H 3N1, Canada
Department of Pediatrics, University of Melbourne Royal Children's Hospital, Parkville, VIC 3052, Australia
The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3084, Australia
Division of Neurology, Epilepsy Genetics Program, Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada
Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada
Issue Date: 2-Nov-2017
Citation: American journal of human genetics 2017; 101(5): 664-685
Abstract: Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18373
DOI: 10.1016/j.ajhg.2017.09.008
ORCID: 0000-0002-2311-2174
0000-0003-4580-841X
PubMed URL: 29100083
Type: Journal Article
Meta-Analysis
Subjects: CLTC
DHDDS
GABBR2
GABRB2
NTRK2
NUS1
RAB11
SNAP25
epileptic encephalopathy
Appears in Collections:Journal articles

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