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Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy
Author(s) -
Lal Dennis,
Trucks Holger,
Møller Rikke S.,
Hjalgrim Helle,
Koeleman Bobby P. C.,
Kovel Carolien G. F.,
Visscher Frank,
Weber Yvonne G.,
Lerche Holger,
Becker Felicitas,
Schankin Christoph J.,
Neubauer Bernd A.,
Surges Rainer,
Kunz Wolfram S.,
Zimprich Fritz,
Franke Andre,
Illig Thomas,
Ried Janina S.,
Leu Costin,
Nürnberg Peter,
Sander Thomas
Publication year - 2013
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12084
Subject(s) - idiopathic generalized epilepsy , penetrance , genetics , biology , exon , gene , epilepsy , phenotype , neuroscience
Summary Purpose Structural variations disrupting the gene encoding the neuron‐specific splicing regulator RBFOX 1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the R bfox1 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 ( IGE s), representing the largest group of genetically determined epilepsies. Methods 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 (q PCR ). Key Findings 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 . Significance 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.