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Lal, D.* ; Ruppert, A.K.* ; Trucks, H.* ; Schulz, H.* ; de Kovel, C.G.F.* ; Kasteleijn-Nolst Trenité, D.* ; Sonsma, A.C.* ; Koeleman, B.P.* ; Lindhout, D.* ; Weber, Y.G.* ; Lerche, H.* ; Kapser, C.* ; Schankin, C.J.* ; Kunz, W.S.* ; Surges, R.* ; Elger, C.E.* ; Gaus, V.* ; Schmitz, B.* ; Helbig, I.* ; Muhle, H.* ; Stephani, U.* ; Klein, K.M.* ; Rosenow, F.* ; Neubauer, B.A.* ; Reinthaler, E.M.* ; Zimprich, F.* ; Feucht, M.* ; Møller, R.S.* ; Hjalgrim, H.* ; de Jonghe, P.* ; Suls, A.* ; Lieb, W.* ; Franke, A.* ; Strauch, K. ; Gieger, C. ; Schurmann, C.* ; Schminke, U.* ; Nürnberg, P.* ; Sander, T.*

Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.

PLoS Genet. 11:e1005226 (2015)

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Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Autism Spectrum Disorder; Copy Number Variants; Genome-wide Association; Of-function Mutations; Epileptic Encephalopathy; Developmental Delay; Intellectual Disability; 15q13.3 Microdeletions; 16p13.11 Predispose; Common Epilepsies

ISSN (print) / ISBN 1553-7390

e-ISSN 1553-7404

Journal PLoS Genetics

Quellenangaben Volume: 11, Issue: 5, Article Number: e1005226

Publisher Public Library of Science (PLoS)

Publishing Place San Francisco

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology II (EPI2)