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

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 syndrome
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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Author:Dennis Lal, Ann-Kathrin Ruppert, Holger Trucks, Herbert Schulz, Carolien G. de Kovel, Dorothée G. Kasteleijn-Nolst Trenité, Anja C. M. Sonsma, Bobby P. Koeleman, Dick Lindhout, Yvonne G. Weber, Holger Lerche, Claudia Kapser, Christoph Josef Schankin, Wolfram S. Kunz, Rainer Surges, Christian Erich Elger, Verena Gaus, Bettina Schmitz, Ingo Helbig, Hiltrud Muhle, Ulrich Stephani, Karl Martin Klein, Felix Rosenow, Bernd Axel Neubauer, Eva Maria Reinthaler, Fritz Zimprich, Martha Feucht, Rikke S. Møller, Helle Hjalgrim, Peter De Jonghe, Arvid Suls, Wolfgang Lieb, Andre Franke, Konstantin Strauch, Christian Gieger, Claudia Schurmann, Ulf Schminke, Peter Nürnberg, Thomas Sander
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25950944
Parent Title (English):Plos Genetics
Place of publication:Lawrence, Kan.
Document Type:Article
Date of Publication (online):2015/05/07
Date of first Publication:2015/05/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Creating Corporation: EPICURE Consortium
Release Date:2015/08/07
Issue:(5): e1005226
First Page:1
Last Page:21
Copyright: © 2015 Lal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
HeBIS PPN:370113861
Dewey Decimal Classification:610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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