Journal
PLOS GENETICS
Volume 11, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1005226
Keywords
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Funding
- European Community [LSHM-CT-2006-037315, 602531]
- German Research Foundation (DFG) within the EUROCORES Programme EuroEPINOMICS [Le1030/11-1, NU50/8-1, SA434/5-1, SA434/4-2]
- German Federal Ministry of Education and Research, National Genome Research Network [NGFNplus: EMINet] [01GS08120, 01GS08123]
- Netherlands National Epilepsy Fund [04-08]
- Netherlands Organization for Scientific Research [917.66.315]
- Fund for Scientific Research Flanders (FWO)
- PopGen biobank
- German Federal Ministry of Education and Research [01EY1103]
- Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research
- State of Bavaria
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0701, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg-West Pomerania
- Austrian Science Fund (FWF) [I 643] Funding Source: researchfish
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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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