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Article dans une revue

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 19 Stéphane Auvin 20 Caroline Nava 21 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 22 Guy D’anjou Guillaume Bourque 23 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 24 Ingrid E. Scheffer Heather C. Mefford 1 Danielle M. Andrade Elsa Rossignol Berge A. Minassian 25, * Jacques L. Michaud 26, *
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.
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Soumis le : mercredi 10 janvier 2018 - 14:51:35
Dernière modification le : mercredi 26 janvier 2022 - 12:58:02

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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, Elsevier (Cell Press), 2017, 101 (5), pp.664 - 685. ⟨10.1016/j.ajhg.2017.09.008⟩. ⟨hal-01680255⟩



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