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

Fadi Hamdan , Candace T. Myers (1) , Patrick Cossette (2) , Philippe Lemay , Dan Spiegelman , Alexandre Dionne Laporte , Christina Nassif , Ousmane Diallo , Jean Mo , Maxime Cadieux-Dion , Sylvia Dobrzeniecka , Caroline Meloche , Kyle Retterer , Megan T. Cho , Jill A. Rosenfeld (3) , Weimin Bi , Christine Massicotte , Marguerite Miguet (4) , Ledia Brunga , Brigid M. Regan , Kelly Mo , Cory Tam , Amy Schneider , Georgie Hollingsworth , David R. Fitzpatrick , Alan Donaldson (5) , Natalie Canham , Edward Blair (6) , Bronwyn Kerr (7) , Andrew E. Fry , Rhys H. Thomas , Joss Shelagh , Jane A. Hurst , Helen Brittain , Moira Blyth , Robert Roger Lebel (8) , 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 (9, 10, 11) , Ange-Line Bruel (9, 10, 11) , Alain Verloes (12) , Katrin Ounap (13) , Monica H. Wojcik , Dara V.F. Albert , Sunita Venkateswaran , Tyson Ware , Dean Jones , Yu-Chi Liu (14) , Shekeeb S. Mohammad , Peyman Bizargity , Carlos A. Bacino , Vincenzo Leuzzi (15) , Simone Martinelli , Bruno Dallapiccola (16) , Marco Tartaglia (17) , Lubov Blumkin , Klaas J. Wierenga , Gabriela Purcarin , James J. O’byrne , Sylvia Stockler , Anna Lehman , Boris Keren (18) , Marie-Christine Nougues , Cyril Mignot (18) , Stéphane Auvin (19) , Caroline Nava (20) , Susan M. Hiatt , Martina Bebin , Yunru Shao , Fernando Scaglia , Seema R. Lalani , Richard E. Frye , Imad T. Jarjour , Stéphanie Jacques , Myriam Boucher , Emilie Riou , Myriam Srour , Lionel Carmant , Anne Lortie , Philippe Major , Paola Diadori , François Dubeau (21) , Guy D’anjou , Guillaume Bourque (22) , 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 (23) , Ingrid E. Scheffer , Heather C. Mefford (1) , Danielle M. Andrade , Elsa Rossignol , Berge A. Minassian (24) , Jacques L. Michaud (25)

1 Division of Genetic Medicine [Seattle]
2 Centre hospitalier universtaire de Montréal
3 BCM - Baylor College of Medicine
4 Laboratoire de Diagnostic Génétique
5 Clinical Genetics Department
6 Department of Clinical Genetics, Oxford Regional Genetics Service
7 Regional Genetic Service, St Mary's Hospital, Manchester
8 SUNY Upstate Medical University
9 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
10 Equipe GAD (LNC - U1231)
11 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
12 Hôpital Robert Debré
13 University Hospital Leipzig = Universitätsklinikum Leipzig
14 Institute of Plant and Microbial Biology
15 Istituto di Genetica Medica
16 Medical Genetics and Pediatric Cardiology
17 Ematologia, Oncologia e Medicina Molecolare
18 CHU Pitié-Salpêtrière [AP-HP]
19 PPAV - "Personal Protection Against Vectors" working group
20 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
21 UdeS - Département de mathématiques [Sherbrooke]
22 McGill University and Genome Quebec Innovation Centre
23 Center of Excellence in Neuromics, University of Montreal
24 SickKids - The Hospital for sick children [Toronto]
25 CHU Sainte Justine [Montréal]

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.

Mots clés: severe intellectual disability; nogo-b receptor; cis-prenyltransferase; diphosphate synthase; medical genetics; structural basis; disorders; disease; glycosylation; children

Domaines: Médecine humaine et pathologie

Fadi Hamdan, Candace T. Myers, Patrick Cossette, Philippe Lemay, Dan Spiegelman, et al.. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. American Journal of Human Genetics, 2017, 101 (5), pp.664 - 685. ⟨10.1016/j.ajhg.2017.09.008⟩. ⟨hal-01680255⟩