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Lal, D.* ; Trucks, H.* ; Møller, R.S.* ; Hjalgrim, H.* ; Koeleman, B.P.* ; 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 (*) ; EPICURE Consortium (*)

Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.

Epilepsia 54, 265-271 (2013)
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PURPOSE: 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. 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 (qPCR). 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Idiopathic Generalized Epilepsy ; Microdeletion ; Rbfox1 ; Genetics; Genome-wide Association ; Copy Number Variants ; Neuropsychiatric Disorders ; 15q13.3 Microdeletions ; 16p13.11 Predispose ; Mental-retardation ; Phenotypes ; Brain ; Scn8a ; Fox-1
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0013-9580
e-ISSN 1528-1167
Journal Epilepsia
Quellenangaben Volume: 54, Issue: 2, Pages: 265-271 Article Number: , Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed
Institute(s) Research Unit Molecular Epidemiology (AME)
Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504200-001
G-504100-001
PubMed ID 23350840
DOI 10.1111/epi.12084
WOS ID WOS:000314750200009
Scopus ID 84873407345
Erfassungsdatum 2013-03-04
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