Exon‐disrupting deletions of NRXN1 in idiopathic generalized epilepsy

Abstract

SUMMARYPurpose: 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). Methods: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays.Key Findings: 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. Significance: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Rare variants in γ‐aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes

“…43 Similarly, an incomplete penetrance has previously been noted for other genetic variants associated with RE (mutations in GRIN2A, DEPDC5, or RBFOX1 or 16p11.2 duplications) 8,[11][12][13] or other epilepsies (15q11.2, 15q13.3, 16p13.3, NRXN1, RBFOX1). [44][45][46] Our observation of a GRIN2A mutation and a 15q11.2 duplication segregating in 2 of the families as a second genetic risk factor in addition to the GABRG2 mutation also deserves attention, as a similar co-occurrence of 2 pathogenic mutations has been reported before for combinations of GRIN2A mutations, DEPDC5 mutations, and 16p11.2 duplications in the context of RE/ARE. 8,11,13 Both of these findings (ie, the incomplete penetrance and the detection of several risk genes in individual patients) are in good agreement with the emerging view that the genetic architecture of RE (and other idiopathic epilepsies) is polygenic and complex.…”

Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies

“…Whether this enrichment is also found in other types of common epilepsies has not yet been evaluated. Previous results support non-recurrent microdeletions in RBFOX1,22 24 25 NRXN126 and GRIN2A7 8 in candidate gene studies in various epilepsies. However, a genome-wide comparison for shared or subtype-specific deleted genes in GGE, RE and AFE has not yet been conducted.…”

Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies

“…Whether this enrichment is also found in other types of common epilepsies has not yet been evaluated. Previous results support nonrecurrent deletions in RBFOX1 [20][21][22], NRXN1 [23], and GRIN2A [7 24] in candidate gene studies in GGE/RE/AFE, GGE, and RE, respectively. However, a genome-wide comparison for shared or subtype specific deleted genes in GGE, RE, and AFE has not been conducted.…”