Targeted resequencing of 101 known and candidate epilepsy genes in 600 patients with severe epilepsies identifies recurrently mutated genes. G. L. Carvill1, S. B. Heavin2, J. M. McMahon2, B. J. O'Roak3, S. F. Berkovic2, J. Shendure3, I. E. Scheffer2, H. C. Mefford1 1) Pediatrics, University of Washington, Seattle, WA; 2) Epilepsy Research Center and Department of Medicine, University of Melbourne, Austin Health, Australia; 3) Department of Genome Sciences, University of Washington, Seattle, WA 98195.

   Epilepsy is one of the most common neurological disorders, with a lifetime incidence of 3%. The epileptic encephalopathies (EE) are the most severe of all the epilepsies, characterized by multiple refractory seizure types, cognitive arrest or regression, and a poor developmental prognosis. While de novo mutations in several genes cause EE, the genetic etiology of the vast majority remain unknown. Using molecular inversion probes for targeted capture followed by multiplexed next generation sequencing, we recently sequenced 19 known EE genes and 46 candidate genes in 500 EE patients (Carvill et al., 2013). Candidate genes were selected from epilepsy-associated CNVs (n=33) and mutations that cause related neurodevelopmental disorders (NDDs) (n=13). Using this approach we made a genetic diagnosis in 10% of our cohort. Importantly, we describe six new EE genes, including CHD2 and SYNGAP1 that each account for ~1% of cases. We have since increased our epilepsy cohort to include well over 600 patients, including additional probands with EE (n=66) and patients with intellectual disability with genetic generalized epilepsy (n=52). We have expanded our target genes to include six recently reported EE genes and 30 new candidate genes for gene discovery, including genes identified by whole exome sequencing (n=8), CNV candidates (n=3), NDD-associated genes (n=7) and members of novel gene families important in EE (n=12). Preliminary results from our expanded study demonstrate emerging trends in genetic heterogeneity, with some genes causing discrete phenotypes. For example, mutations in GRIN2A cause epilepsy aphasia syndromes, and GABRA1 mutations cause Dravet syndrome. By contrast, de novo mutations in other genes, including CHD2, SYNGAP1, SCN8A and SCN2A are implicated in a wider range of EE and NDD phenotypes. Of note, 4/6 new genes we describe are not directly involved in the regulation of neurotransmission at the synapse. CHD2, MBD5 and MEF2C genes are involved in regulation of chromatin states that control gene expression, while HNRNPU is involved in splicing. These novel biological functions provide new avenues of research for understanding disease mechanisms and development of targeted therapies. In conclusion, we present a cost-effective, efficient method of screening multiple EE genes in large cohorts that will transform molecular diagnosis and highlight novel biological pathways implicated in epileptogenesis that can be targeted in therapeutic approaches.

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