1. De novo variants in neurodevelopmental disorders with epilepsy
- Author
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Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Moller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., Afawi, Z., De Kovel, C., Dimova, P., Djemie, T., Endziniene, M., Hoffman-Zacharska, D., Jahn, J., Korff, C., Lehesjoki, A. -E., Marini, C., Muller, S. H., Pal, D., Schwarz, N., Selmer, K., Serratosa, J., Stephani, U., Sterbova, K., Suls, A., Syrbe, S., Talvik, I., Von Spiczak, S., Zara, F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., Lemke, J. R., Children's Hospital, Lastenneurologian yksikkö, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Research Programme for Molecular Neurology, Neuroscience Center, HUS Children and Adolescents, Genomics of Neurological and Neuropsychiatric Disorders, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Korff, Christian, and EuroEPINOMICS RES Consortium
- Subjects
Exome/genetics ,Male ,0301 basic medicine ,ILAE COMMISSION ,Joint analysis ,Neurodevelopmental Disorders/genetics ,Bioinformatics ,Epilepsy/genetics ,Epilepsy ,0302 clinical medicine ,Intellectual disability ,SEQUENCE VARIANTS ,Missense mutation ,Epilepsy is a frequent feature ,Exome ,TERMINOLOGY ,Disease gene ,0303 health sciences ,ddc:618 ,medicine.diagnostic_test ,Genetic Predisposition to Disease/genetics ,Neurodevelopmental disorders ,1184 Genetics, developmental biology, physiology ,HUMAN-DISEASE ,PREVALENCE ,3. Good health ,Genetic Variation/genetics ,De novo variants ,Female ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] ,Genetic Testing/methods ,Disease Association ,Biology ,CLASSIFICATION ,03 medical and health sciences ,Intellectual Disability ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Limited evidence ,030304 developmental biology ,Genetic testing ,business.industry ,MUTATIONS ,AUTISM SPECTRUM DISORDER ,Genetic Variation ,medicine.disease ,Intellectual Disability/genetics ,030104 developmental biology ,Neurodevelopmental Disorders ,epilepsy ,KCNQ2 ENCEPHALOPATHY ,Human medicine ,3111 Biomedicine ,business ,Genetic diagnosis ,030217 neurology & neurosurgery - Abstract
Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.
- Published
- 2018