Journal Article

De novo variants in neurodevelopmental disorders with epilepsy

Stamberger, Hannah, Koeleman, Bobby P. C., Caglayan, Hande, Helbig, Ingo, Kosmicki, Jack A., May, Patrick, Weber, Yvonne G., Weckhuysen, Sarah, Poduri, Annapurna, Abou Jamra, Rami, Heyne, Henrike O., De Jonghe, Peter, Pendziwiat, Manuela, Møller, Rikke S., Tang, Sha, Wu, Sitao, Striano, Pasquale, Sisodiya, Sanjay M., Singh, Tarjinder, Linnankivi, Tarja, Helbig, Katherine L., Craiu, Dana, Lal, Dennis, Daly, Mark J., Palotie, Aarno, Neubauer, Bernd A., Guerrini, Renzo, Lemke, Johannes R., Muhle, Hiltrud

2018

Overview

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. Analysis of individuals with neurodevelopmental disorders (NDDs) with epilepsy identifies 33 genes with a significant excess of de novo variants. Comparison of rates of de novo variants between NDDs with or without epilepsy highlights differences between these phenotypic groups.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208 / 631/208/212 / 692/699/375/178 / 692/699/375/366 / Agriculture / Analysis / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Disease control / Disorders / Epilepsy / Epilepsy - genetics / Exome - genetics / Female / Gene Function / Genes / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetic research / Genetic screening / Genetic testing / Genetic Testing - methods / Genetic variation / Genetic Variation - genetics / Genomics / Human Genetics / Humans / Intellectual disabilities / Intellectual Disability - genetics / Male / Medical schools / Mutation / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurophysiology / Offspring / Phenotypes / SNAP-25 protein