Abstracts

Rationale: Epilepsy, characterized by recurrent unprovoked seizures, is one of the most common neurological disorders and is a highly phenotypic and genetic heterogeneous disorder with many genes associated to the disease reported mainly in the Caucasian population. Limited research has been conducted to identify genetic contributors to epilepsy in the Hispanics/Latino population. The results of genome-wide association studies (GWAS) and meta-analyses have offered important clues of specific variants contributing to the vulnerability to epilepsy, however, progress in extending beyond identification of pathogenic mutations is very slow. Whole exome sequencing, as a rapid and reliable means, has identified causative mutations responsible for a number of rare and common diseases. Therefore, we applied WES to identify pathogenic mutations for epilepsy in the Hispanic population. Methods: All 14 affected subjects (5 males, 9 females) with epilepsy [a1] from the Latino were recruited from the outpatient clinic of the Departments of Psychiatry and Neurology at the Texas Tech University Health Sciences Center in El Paso, Texas. The patients had met and will meet the diagnosis criteria for epilepsy. Whole-exome sequencing was performed in 14 patients with epilepsy by the Illumina Nextera Rapid Capture Exome Enrichment kits (Illumina, FC-140-1001) on an Illumina MiSeq. Then bioinformatic prediction was done using the SVS program (Golden Helix ®) by accessing data from dbNSFP, which provides scores from multiple functional prediction programs (sift, Polyphen2, Mutation Taster, MutationAssessor, and fathmm) as well as two conservation scores (GERP++ and PhyloP). Results: Of the 14 adult patients with epilepsy, 47,392 variants within exons or at splice-site boundaries on chromosomes were identified and after filtering, 53 non-synonymous rare variants were identified. To identify high impact genes, literature-based filter method was used to narrow down the gene list to four gene mutations: CYP21A2, HERC2, RASGRP1, and CREBBP. These genes are involved in cellular transport, catabolic processes and nucleotide metabolism and may be important in the pathophysiology of epilepsy. Among these four genes, a mutation in the CREBBP gene was identified as a de novo mutation in a subtype of epileptic encephalopathies in a recent study. Conclusions: WES led to the discovery of additional epilepsy genes in the Latino population; however, future validation and segregation analysis using a family design are needed to confirm the current findings.