Abstracts

Rationale: Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts we aimed to confirm the association of 15q13 deletions and IGE. In addition we sought to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for the 15q13.3 microdeletion carriers in familial cases. Methods: Test methods used were quantitative PCR or SNP arrays and positive results were confirmed by array Comparative Genomic Hybridization (CGH) analysis using probes specific to the 15q13.3 region. Results: The microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE. The inheritance of this lesion was tracked using family studies. Of the 7 microdeletions identified, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrant carriers were identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families. Conclusions: The 15q13.3 microdeletion in IGE is acting as a risk factor consistent with the common-disease, multiple rare-variant hypothesis of complex disease causation. Since the breakpoints map within duplicated sequences that flank the critical region, non-allelic homologous recombination continues to create individuals with nearly identical genetic variation despite that variation being subject to selective pressure. The confirmed association of the 15q13.3 microdeletion with an IGE phenotype and other common brain disorders suggests that structural genomic variation represents an emerging entity contributing to human disorders with complex inheritance.