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. 2015 May 7;11(5):e1005226.
doi: 10.1371/journal.pgen.1005226. eCollection 2015 May.

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

Dennis Lal  1 , Ann-Kathrin Ruppert  2 , Holger Trucks  2 , Herbert Schulz  2 , Carolien G de Kovel  3 , Dorothée Kasteleijn-Nolst Trenité  4 , Anja C M Sonsma  3 , Bobby P Koeleman  3 , Dick Lindhout  5 , Yvonne G Weber  6 , Holger Lerche  6 , Claudia Kapser  7 , Christoph J Schankin  7 , Wolfram S Kunz  8 , Rainer Surges  8 , Christian E Elger  8 , Verena Gaus  9 , Bettina Schmitz  10 , Ingo Helbig  11 , Hiltrud Muhle  11 , Ulrich Stephani  11 , Karl M Klein  12 , Felix Rosenow  12 , Bernd A Neubauer  13 , Eva M Reinthaler  14 , Fritz Zimprich  14 , Martha Feucht  15 , Rikke S Møller  16 , Helle Hjalgrim  16 , Peter De Jonghe  17 , Arvid Suls  17 , Wolfgang Lieb  18 , Andre Franke  19 , Konstantin Strauch  20 , Christian Gieger  21 , Claudia Schurmann  22 , Ulf Schminke  23 , Peter Nürnberg  24 ; EPICURE Consortium; Thomas Sander  2
Collaborators, Affiliations

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

Dennis Lal et al. PLoS Genet. .

Abstract

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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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: BS has received in the last three years research funding from the German Society for Epileptology, UCB Pharma GmbH and Desitin Arzneimittel Deutschland. BS received speakers honoraria from Eisai GmbH, Desitin Arzneimittel Deutschland and UCB Pharma GmbH. The other authors declare no conflict of interest.

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