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.
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We thank all patients and their families who participated in this study, as well as the teams who were involved in recruiting patients and gathering samples and data at the respective study sites. We thank L. Vissers and C. Gilissen for epilepsy and age phenotypes from the cohort of Lelieveld et al.23 and J. McRae for useful discussions on the DDD cohort7. We are grateful to members of the ATGU and the Institute for Human Genetics in Leipzig for insightful discussions. We thank J. Krause for support in figure design and helpful conversations. This work was supported by the Eurocores program EuroEPINOMICS, the Fund for Scientific Research Flanders (FWO), International Coordination Action (ICA) grant G0E8614N, and the University of Antwerp (research fund). H.O.H. was supported by stipends from the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 and the German Research Foundation (DFG): HE7987/1-1. H.S. was supported as a PhD fellow of the Fund for Scientific Research Flanders (1125416 N). I.H. and Y.G.W. were supported by DFG grants WE4896/3-1 and HE5415/6-1. R.G. received funding through the EU Seventh Framework Programme (FP7) under the project DESIRE grant N602531. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.
Supplementary Figures 1–10 and Supplementary Note
Description of cohorts analyzed in this study
List of all DNVmis, DNVtrunc, and DNVsynonymous of all NDD cohorts (n = 6,753) and controls (n = 1,911) analyzed in this study
List of 50 dominant and X-linked known EE genes
Genes with at least two DNVmis+trunc in NDDEE+uE (n = 1,942)
Genes with at least two DNVmis+trunc in all NDD (NDD EE+uE +woE, n = 6,753)
Significantly enriched HPO terms in 33 genes with DNV burden in NDD with epilepsy
Evaluating genes with at least two DNVmis+trunc in NDD with epilepsy for therapeutic consequences
Gene sets significantly enriched (odds raio > 1) or depleted (odds ratio < 1) for DNV in epilepsy compared to no epilepsy
DNV in epilepsy vs. no epilepsy
DNV in NDDuE vs. NDDEE
Diagnostic sequencing panels from 24 different academic and commercial providers
191 dominant/X-linked genes in sequencing panels from 24 different academic/commercial providers with three criteria for disease association in NDD with epilepsy (DNV burden, constraint, brain expression)
Evaluating 50 genes lacking features of DNV-enriched genes (DNV enrichment, constraint, brain expression) for published evidence for disease association using guidelines from the ClinGen Gene Curation Workgroup