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


Hamdan, FF and Myers, CT and Cossette, P and Lemay, P and Spiegelman, D and Laporte, AD and Nassif, C and Diallo, O and Monlong, J and Cadieux-Dion, M and Dobrzeniecka, S and Meloche, C and Retterer, K and Cho, MT and Rosenfeld, JA and Bi, W and Massicotte, C and Miguet, M and Brunga, L and Regan, BM and Mo, K and Tam, C and Schneider, A and Hollingsworth, G and FitzPatrick, DR and Donaldson, A and Canham, N and Blair, E and Kerr, B and Fry, AE and Thomas, RH and Shelagh, J and Hurst, JA and Brittain, H and Blyth, M and Lebel, RR and Gerkes, EH and Davis-Keppen, L and Stein, Q and Chung, WK and Dorison, SJ and Benke, PJ and Fassi, E and Corsten-Janssen, N and Kamsteeg, EJ and Mau-Them, FT and Bruel, AL and Verloes, A and A unap, K and Wojcik, MH and Albert, DVF and Venkateswaran, S and Ware, T and Jones, D and Liu, YC and Mohammad, SS and Bizargity, P and Bacino, CA and Leuzzi, V and Martinelli, S and Dallapiccola, B and Tartaglia, M and Blumkin, L and Wierenga, KJ and Purcarin, G and O'Byrne, JJ and Stockler, S and Lehman, A and Keren, B and Nougues, MC and Mignot, C and Auvin, S and Nava, C and Hiatt, SM and Bebin, M and Shao, Y and Scaglia, F and Lalani, SR and Frye, RE and Jarjour, IT and Jacques, S and Boucher, RM and Riou, E and Srour, M and Carmant, L and Lortie, A and Major, P and Diadori, P and Dubeau, F and D'Anjou, G and Bourque, G and Berkovic, SF and Sadleir, LG and Campeau, PM and Kibar, Z and LafreniA re, RG and Girard, SL and Mercimek-Mahmutoglu, S and Boelman, C and Rouleau, GA, High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies, American journal of human genetics, 101, (5) pp. 664-685. ISSN 0002-9297 (2017) [Refereed Article]

Copyright Statement

Copyright 2017 American Society of Human Genetics.

DOI: doi:10.1016/j.ajhg.2017.09.008


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.

Item Details

Item Type:Refereed Article
Keywords:CLTC, DHDDS, GABBR2, GABRB2, NTRK2, NUS1, RAB11, SNAP25, epileptic encephalopathy
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Ware, T (Dr Tyson Ware)
UTAS Author:Jones, D (Dr Dean Jones)
ID Code:123849
Year Published:2017
Web of Science® Times Cited:244
Deposited By:Medicine
Deposited On:2018-02-02
Last Modified:2022-08-23

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