Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.

Rikke S Møller, Yvonne G Weber, Laura L Klitten, Holger Trucks, Hiltrud Muhle, Wolfram S Kunz, Heather C Mefford, Andre Franke, Monika Kautza, Peter Wolf, Dieter Dennig, Stefan Schreiber, Ina-Maria Rückert, H-Erich Wichmann, Jan P Ernst, Claudia Schurmann, Hans J Grabe, Niels Tommerup, Ulrich Stephani, Holger Lerche, Helle Hjalgrim, Ingo Helbig, Thomas Sander, - -
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Epilepsia (Copenhagen)
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We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE.We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs).We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays.