TY  - JOUR
A1  - Lal, Dennis
A1  - Ruppert, Ann-Kathrin
A1  - Trucks, Holger
A1  - Schulz, Herbert
A1  - Kovel, Carolien G. de
A1  - Kasteleijn-Nolst Trenité, Dorothée G.
A1  - Sonsma, Anja C. M.
A1  - Koeleman, Bobby P.
A1  - Lindhout, Dick
A1  - Weber, Yvonne G.
A1  - Lerche, Holger
A1  - Kapser, Claudia
A1  - Schankin, Christoph Josef
A1  - Kunz, Wolfram S.
A1  - Surges, Rainer
A1  - Elger, Christian Erich
A1  - Gaus, Verena
A1  - Schmitz, Bettina
A1  - Helbig, Ingo
A1  - Muhle, Hiltrud
A1  - Stephani, Ulrich
A1  - Klein, Karl Martin
A1  - Rosenow, Felix
A1  - Neubauer, Bernd Axel
A1  - Reinthaler, Eva Maria
A1  - Zimprich, Fritz
A1  - Feucht, Martha
A1  - Møller, Rikke S.
A1  - Hjalgrim, Helle
A1  - Jonghe, Peter De
A1  - Suls, Arvid
A1  - Lieb, Wolfgang
A1  - Franke, Andre
A1  - Strauch, Konstantin
A1  - Gieger, Christian
A1  - Schurmann, Claudia
A1  - Schminke, Ulf
A1  - Nürnberg, Peter
A1  - Sander, Thomas
T1  - Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies
T2  - Plos Genetics
N2  - 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.
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/37990
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-379901
SN  - 1553-7404
SN  - 1553-7390
N1  - 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
VL  - 11
IS  - (5): e1005226
SP  - 1
EP  - 21
PB  - PLoS
CY  - Lawrence, Kan.
ER  -