Abstracts

Rationale: Single nucleotide genetic variation is a known source of familial and sporadic disease. Recent evidence shows that the frequency of de novo genomic rearrangements, including copy number variations (CNVs) is about four orders of magnitude greater than the rate of nucleotide-based mutations. The important contribution of CNVs to epilepsy phenotypes is only now being recognized with the application of array based whole genome comparative hybridization (aCGH) platforms. Ion channel genes, despite their relative abundance and critical function in the excitable network, have been underrepresented in whole genome scans. Given the high incidence of Mendelian channel variants in epilepsy, we designed a custom CNV chip targeting this candidate gene superfamily, which represents ~1% of the genome. Methods: We developed a custom built ion channel gene-specific comparative hybridization array (ICCH array) that interrogates all known exons in 247 human ion channel subunit genes, and used the chip to screen a cohort of 47 patients with idiopathic epilepsy. Results: We identified 183 duplications affecting 56 channel genes with an average of four duplications per individual, and 169 deletions affecting 30 genes with an average of 3.6 deletions per individual. We observed that chromosomes and genes differed in their likelihood of being affected by CNVs. CNV variation was observed in known human epilepsy genes as well as in ion channel genes previously unlinked to human excitability disorders, thus identifying novel candidate disease genes. Conclusions: Our targeted gene array project is the first to survey all known ion channel genes at high resolution for structural aberrations with unprecedented sensitivity. With the new platform we can move beyond single nucleotide polymorphisms to study a new dimension of genetic variation contributing to epilepsy. The ICCH array represents an innovative, rapid, and cost effective approach for uncovering novel disease mechanisms from a defined gene set and discovering novel ion channel disease genes. Supported by NIH (AG, JLN) and Mcknight Brain Disorders Award (JLN).