Abstracts

Rationale: Epilepsy is one of the most common neurological disorders, with a lifetime incidence of 3%. The epileptic encephalopathies (EEs) are the most severe of all the epilepsies. Patients typically present with refractory epilepsy with multiple seizure types, cognitive arrest or regression, and have a poor prognosis. De novo mutations have been increasingly recognized as causative for these disorders, and mutations in over 30 genes have been described. These gene discovery efforts have highlighted a role for genes involved in chromatin regulation in the pathogenesis of EE, including CHD2, MBD5, MEF2C, FOXG1 and ARX. We aim to identify novel genes for epilepsy by examining genes that are chromatin regulators. Methods: We selected 26 known and candidate genes that act in this process and performed targeted resequencing in a cohort of 868 patients with EEs of unknown cause to identify novel de novo mutations. Results: To date we have completed mutation detection in 703 patients in 21 genes. Thus far we have identified 17 pathogenic mutations in seven genes with at least one novel gene for this group of disorders. Overall, mutations in chromatin regulator genes account for ~2% of cases in our cohort, and about 14% of all mutation positive patients. Our results emphasize the importance of chromatin regulation in the pathogenesis of epilepsy and highlight the need for studies of the pathogenic mechanisms that underlie these conditions. To this end, we used the chromatin remodeler, CHD2, as a model to develop novel epigenomic approaches to studying disease mechanisms. By performing ChIP-seq in four fetal tissues, we identified those target genes that are brain-specific. Integrating this data with chromatin state maps from fetal brain will determine the likely function of CHD2. Conclusions: This experimental paradigm can be expanded to include other epilepsy genes. The role of chromatin remodeling is largely unexplored in epilepsy, but it is a dynamic process with many therapeutic targets, and presents a novel opportunity to develop new treatments for patients.