Members of the EMINet Consortium are in Appendix 1.
Full-Length Original Research
Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy
Version of Record online: 25 JAN 2013
Wiley Periodicals, Inc. © 2013 International League Against Epilepsy
Volume 54, Issue 2, pages 265–271, February 2013
How to Cite
Lal, D., Trucks, H., Møller, R. S., Hjalgrim, H., Koeleman, B. P. C., de Kovel, C. G. F., Visscher, F., Weber, Y. G., Lerche, H., Becker, F., Schankin, C. J., Neubauer, B. A., Surges, R., Kunz, W. S., Zimprich, F., Franke, A., Illig, T., Ried, J. S., Leu, C., Nürnberg, P., Sander, T., EMINet Consortium and EPICURE Consortium (2013), Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia, 54: 265–271. doi: 10.1111/epi.12084
- Issue online: 5 FEB 2013
- Version of Record online: 25 JAN 2013
- Manuscript Accepted: 21 NOV 2012
- European Community. Grant Number: LSHM-CT-2006-037315
- German Research Foundation . Grant Numbers: NE416/5-1, Le1030/11-1, SA434/5-1
- German Federal Ministry of Education and Research
- National Genome Research Network. Grant Numbers: 01GS08120, 01GS08123, TUR 09/I10
- The Netherlands National Epilepsy Fund. Grant Number: 04-08
- The Netherlands Organization for Scientific Research. Grant Number: 917.66.315
- PopGen biobank
- Munich Center of Health Sciences
- Idiopathic generalized epilepsy;
- RBFOX1 ;
Structural variations disrupting the gene encoding the neuron-specific splicing regulator RBFOX1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the Rbfox1 knockout mouse model showed an increased susceptibility of seizures. The present candidate gene study tested whether exon-disrupting deletions of RBFOX1 increase the risk of idiopathic generalized epilepsies (IGEs), representing the largest group of genetically determined epilepsies.
Screening of microdeletions (size: >40 kb, coverage >20 markers) affecting the genomic sequence of the RBFOX1 gene was carried out by high-resolution single-nucleotide polymorphism (SNP) arrays in 1,408 European patients with idiopathic generalized epilepsy (IGE) and 2,256 population controls. Validation of RBFOX1 deletions and familial segregation analysis were performed by quantitative polymerase chain reaction (qPCR).
We detected five exon-disrupting RBFOX1 deletions in the IGE patients, whereas none was observed in the controls (p = 0.008, Fisher's exact test). The size of the exonic deletions ranged from 68 to 896 kb and affected the untranslated 5′-terminal RBFOX1 exons. Segregation analysis in four families indicated that the deletions were inherited, display incomplete penetrance, and heterogeneous cosegregation patterns with IGE.
Rare deletions affecting the untranslated 5′-terminal RBFOX1 exons increase risk of common IGE syndromes. Variable expressivity, incomplete penetrance, and heterogeneous cosegregation patterns suggest that RBFOX1 deletions act as susceptibility factor in a genetically complex etiology, where heterogeneous combinations of genetic factors determine the disease phenotype.