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


RESULTS
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.


CONCLUSIONS
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.
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Dennis
D
Lal
Holger
H
Trucks
Rikke S
RS
Møller
Helle
H
Hjalgrim
Bobby P C
BP
Koeleman
Carolien G F
CG
de Kovel
Frank
F
Visscher
Yvonne G
YG
Weber
Holger
H
Lerche
Felicitas
F
Becker
Christoph J
CJ
Schankin
Bernd A
BA
Neubauer
Rainer
R
Surges
Wolfram S
WS
Kunz
Fritz
F
Zimprich
Andre
A
Franke
Thomas
T
Illig
Janina S
JS
Ried
Costin
C
Leu
Peter
P
Nürnberg
Thomas
T
Sander
D020121:5' Untranslated Regions; D017668:Age of Onset; D016022:Case-Control Studies; D002648:Child; D015897:Comorbidity; D004247:DNA / Q000235:genetics; D004829:Epilepsy, Generalized / Q000453:epidemiology / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*; D044465:White People
D020121:5' Untranslated Regions; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D004247:DNA