High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Fadi F. Hamdan; Candace T. Myers; Patrick Cossette; Philippe Lemay; Dan Spiegelman; Alexandre Dionne Laporte; Christina Nassif; Ousmane Diallo; Jean Monlong; Maxime Cadieux-Dion; Sylvia Dobrzeniecka; Caroline Meloche; Kyle Retterer; Megan T. Cho; Jill A. Rosenfeld; Weimin Bi; Christine Massicotte; Marguerite Miguet; Ledia Brunga; Brigid M. Regan; Kelly Mo; Cory Tam; Amy Schneider; Georgie Hollingsworth; David R. FitzPatrick; Alan Donaldson; Natalie Canham; Edward Blair; Bronwyn Kerr; Andrew E. Fry; Rhys H. Thomas; Joss Shelagh; Jane A. Hurst; Helen Brittain; Moira Blyth; Robert Roger Lebel; Erica H. Gerkes; Laura Davis-Keppen; Quinn Stein; Wendy K. Chung; Sara J. Dorison; Paul J. Benke; Emily Fassi; Nicole Corsten-Janssen; Erik-Jan Kamsteeg; Frederic T. Mau-Them; Ange-Line Bruel; Alain Verloes; Katrin Õunap; Monica H. Wojcik; Dara V.F. Albert; Sunita Venkateswaran; Tyson Ware; Dean Jones; Yu-Chi Liu; Shekeeb S. Mohammad; Peyman Bizargity; Carlos A. Bacino; Vincenzo Leuzzi; Simone Martinelli; Bruno Dallapiccola; Marco Tartaglia; Lubov Blumkin; Klaas J. Wierenga; Gabriela Purcarin; James J. O’Byrne; Sylvia Stockler; Anna Lehman; Boris Keren; Marie-Christine Nougues; Cyril Mignot; Stéphane Auvin; Caroline Nava; Susan M. Hiatt; Martina Bebin; Yunru Shao; Fernando Scaglia; Seema R. Lalani; Richard E. Frye; Imad T. Jarjour; Stéphanie Jacques; Renee-Myriam Boucher; Emilie Riou; Myriam Srour; Lionel Carmant; Anne Lortie; Philippe Major; Paola Diadori; François Dubeau; Guy D’Anjou; Guillaume Bourque; Samuel F. Berkovic; Lynette G. Sadleir; Philippe M. Campeau; Zoha Kibar; Ronald G. Lafrenière; Simon L. Girard; Saadet Mercimek-Mahmutoglu; Cyrus Boelman; Guy A. Rouleau; Ingrid E. Scheffer; Heather C. Mefford; Danielle M. Andrade; Elsa Rossignol; Berge A. Minassian; Jacques L. Michaud; Deciphering Developmental Disorders Study

doi:10.1016/j.ajhg.2017.09.008

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High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Journal article

Peer reviewed

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Fadi F. Hamdan, Candace T. Myers, Patrick Cossette, Philippe Lemay, Dan Spiegelman, Alexandre Dionne Laporte, Christina Nassif, Ousmane Diallo, Jean Monlong, Maxime Cadieux-Dion, …

American journal of human genetics, Vol.101(5), pp.664-685

2017-11-02

DOI: https://doi.org/10.1016/j.ajhg.2017.09.008

PMCID: PMC5673604

PMID: 29100083

Abstract

CLTC

DHDDS

epileptic encephalopathy

GABBR2

GABRB2

NTRK2

NUS1

RAB11

SNAP25

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.68 Lipids; 1.68.1273 Smith-Lemli-Opitz Syndrome
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Details

Title: High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
Creators: Fadi F. Hamdan - Centre Hospitalier Universitaire Sainte-Justine
Candace T. Myers - University of Washington
Patrick Cossette - University of Montreal
Philippe Lemay - Centre Hospitalier Universitaire Sainte-Justine
Dan Spiegelman - Montreal Neurological Institute and Hospital
Alexandre Dionne Laporte - Montreal Neurological Institute and Hospital
Christina Nassif - Centre Hospitalier Universitaire Sainte-Justine
Ousmane Diallo - Montreal Neurological Institute and Hospital
Jean Monlong - McGill University
Maxime Cadieux-Dion - University of Montreal
Sylvia Dobrzeniecka - University of Montreal
Caroline Meloche - University of Montreal
Kyle Retterer - GeneDx
Megan T. Cho - GeneDx
Jill A. Rosenfeld - Baylor College of Medicine
Weimin Bi - Baylor College of Medicine
Christine Massicotte - Centre Hospitalier Universitaire Sainte-Justine
Marguerite Miguet - Centre Hospitalier Universitaire Sainte-Justine
Ledia Brunga - University of Toronto
Brigid M. Regan - Toronto Western Hospital
Kelly Mo - Toronto Western Hospital
Cory Tam - Toronto Western Hospital
Amy Schneider - University of Melbourne
Georgie Hollingsworth - University of Melbourne
David R. FitzPatrick - Western General Hospital
Alan Donaldson - University Hospitals Bristol NHS Foundation Trust
Natalie Canham - London North West Healthcare NHS Trust
Edward Blair - Nuffield Orthopaedic Centre
Bronwyn Kerr - Central Manchester University Hospitals NHS Foundation Trust
Andrew E. Fry - University Hospital of Wales
Rhys H. Thomas - Cardiff University
Joss Shelagh - West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK
Jane A. Hurst - Great Ormond Street Hospital
Helen Brittain - Great Ormond Street Hospital
Moira Blyth - Leeds Teaching Hospitals NHS Trust
Robert Roger Lebel - SUNY Upstate Medical University
Erica H. Gerkes - University Medical Center Groningen
Laura Davis-Keppen - University of South Dakota
Quinn Stein - Augustana-Sanford Genetic Counseling Graduate Program, Sioux Falls, SD 57197, USA
Wendy K. Chung - Columbia University Irving Medical Center
Sara J. Dorison - Baptist Memorial Hospital
Paul J. Benke - Boston Children's Hospital
Emily Fassi - Washington University in St. Louis
Nicole Corsten-Janssen - University Medical Center Groningen
Erik-Jan Kamsteeg - Radboud University Nijmegen
Frederic T. Mau-Them - University of Burgundy
Ange-Line Bruel - University of Burgundy
Alain Verloes - Genetics Department, Assistance Publique – Hôpitaux de Paris, Robert-Debré University Hospital, 75000 Paris, France
Katrin Õunap - Tartu University Hospital
Monica H. Wojcik - Broad Institute
Dara V.F. Albert - Nationwide Children's Hospital
Sunita Venkateswaran - Children's Hospital of Eastern Ontario
Tyson Ware - University of Tasmania
Dean Jones - University of Tasmania
Yu-Chi Liu - University of Melbourne
Shekeeb S. Mohammad - Children's Hospital at Westmead
Peyman Bizargity - Baylor College of Medicine
Carlos A. Bacino - Baylor College of Medicine
Vincenzo Leuzzi - Sapienza University of Rome
Simone Martinelli - Istituto Superiore di Sanità
Bruno Dallapiccola - Boston Children's Hospital
Marco Tartaglia - Boston Children's Hospital
Lubov Blumkin - Wolfson Medical Center
Klaas J. Wierenga - University of Oklahoma Health Sciences Center
Gabriela Purcarin - University of Oklahoma Health Sciences Center
James J. O’Byrne - University of British Columbia, BC Children’s Hospital, Vancouver, BC V6H 3N1, Canada
Sylvia Stockler - University of British Columbia
Anna Lehman - University of British Columbia
Boris Keren - Sorbonne University
Marie-Christine Nougues - Assistance Publique – Hôpitaux de Paris, Hôpital d’Enfants Armand Trousseau, Service de Neuropédiatrie, Paris 75012, France
Cyril Mignot - Sorbonne University
Stéphane Auvin - Délégation Paris 7
Caroline Nava - Sorbonne University
Susan M. Hiatt - Joint Genome Institute
Martina Bebin - Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Yunru Shao - Baylor College of Medicine
Fernando Scaglia - Baylor College of Medicine
Seema R. Lalani - Baylor College of Medicine
Richard E. Frye - University of Arkansas for Medical Sciences
Imad T. Jarjour - Baylor College of Medicine
Stéphanie Jacques - Centre Hospitalier Rouyn-Noranda, Rouyn-Noranda, QC J9X 2B2, Canada
Renee-Myriam Boucher - Division of Neurology, Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada
Emilie Riou - Centre Hospitalier Universitaire de Sherbrooke
Myriam Srour - McGill University
Lionel Carmant - University of Montreal
Anne Lortie - University of Montreal
Philippe Major - University of Montreal
Paola Diadori - University of Montreal
François Dubeau - Montreal Neurological Institute and Hospital
Guy D’Anjou - Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada
Guillaume Bourque - McGill University
Samuel F. Berkovic - University of Melbourne
Lynette G. Sadleir - University of Otago
Philippe M. Campeau - Université de Montréal
Zoha Kibar - University of Montreal
Ronald G. Lafrenière - University of Montreal
Simon L. Girard - McGill University
Saadet Mercimek-Mahmutoglu - University of Toronto
Cyrus Boelman - University of British Columbia
Guy A. Rouleau - Montreal Neurological Institute and Hospital
Ingrid E. Scheffer - University of Melbourne
Heather C. Mefford - University of Washington
Danielle M. Andrade - Toronto Western Hospital
Elsa Rossignol - University of Montreal
Berge A. Minassian - University of Toronto
Jacques L. Michaud - University of Montreal
Deciphering Developmental Disorders Study
Publication Details: American journal of human genetics, Vol.101(5), pp.664-685
Publisher: Elsevier Inc
Academic Unit: Benefits - Other; Human Resources
Language: English
Resource Type: Journal article
PMID: 29100083
PMCID: PMC5673604
Record Identifier: 991031739964902976