Epilepsy, Idiopathic Generalized, Susceptibility To, 7

For a phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy (IGE), see 600669.

Juvenile myoclonic epilepsy (JME; see 254770) is a form of idiopathic generalized epilepsy.

Elmslie et al. (1997) tested for linkage between JME and chromosomal regions harboring genes for nAChR subunits in 34 pedigrees using parametric and nonparametric analyses. Strong evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region containing the gene that encodes the alpha-7 subunit of nAChR (CHRNA7; 118511), which maps to chromosome 15q14. Elmslie et al. (1997) suggested that this major locus (EJM2) contributes to genetic susceptibility to JME in a majority of the families studied.

Sander et al. (1997) found no evidence supporting linkage of JME to any chromosome 15 loci.

Helbig et al. (2009) identified a 15q13.3 microdeletion (see 612001) in 12 of 1,223 patients with idiopathic generalized epilepsy, including childhood and juvenile absence seizures, juvenile myoclonic seizures, and primary generalized tonic-clonic seizures. The microdeletion was not observed in 3,699 controls (p = 5.32 x 10(-8)). One of the 12 probands had severe intellectual disability, and 2 had mild intellectual disability; the remaining 9 had no dysmorphic features or intellectual disability. None of the patients suffered a psychotic episode. Four of 7 first-degree relatives with the deletion had seizures, panic disorder, or intellectual disability. Helbig et al. (2009) implicated the CHRNA7 gene. The authors concluded that the 15q13.3 microdeletion can underlie a range of neuropsychiatric disorders, and noted that in their study it was responsible for about 1% of cases with IGE.

Dibbens et al. (2009) identified a 15q13.3 microdeletion in 7 (1.3%) of 539 unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization (CGH) analysis using probes specific to the 15q13.3 region. Of the 7 microdeletions identified in probands, 3 were de novo, 2 were transmitted from an unaffected parent, and in 2 cases the parents were unavailable. Nonpenetrance of the microdeletion was identified in 4 of 7 pedigrees, and 3 pedigrees included other family members with IGE who lacked the 15q13.3 deletion. When combined with the results of Helbig et al. (2009), the odds ratio is 68.2 (95% CI 29-181, p less than 2.2 x 10(-16)), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families.