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Nat Genet DOI:10.1038/s41588-018-0143-7

De novo variants in neurodevelopmental disorders with epilepsy.

Publication TypeJournal Article
Year of Publication2018
AuthorsHeyne, HO, Singh, T, Stamberger, H, Jamra, RAbou, Caglayan, H, Craiu, D, De Jonghe, P, Guerrini, R, Helbig, KL, Koeleman, BPC, Kosmicki, JA, Linnankivi, T, May, P, Muhle, H, Møller, RS, Neubauer, BA, Palotie, A, Pendziwiat, M, Striano, P, Tang, S, Wu, S, Poduri, A, Weber, YG, Weckhuysen, S, Sisodiya, SM, Daly, MJ, Helbig, I, Lal, D, Lemke, JR
Corporate AuthorsEuroEPINOMICS RES Consortium
JournalNat Genet
Date Published2018 07
KeywordsEpilepsy, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.


Alternate JournalNat Genet
PubMed ID29942082
Grant ListMR/J011231/1 / MRC_ / Medical Research Council / United Kingdom