Exome sequencing of mesial temporal lobe epilepsy with hippocampal sclerosis in parent-offspring trios

Abstract

Mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) is recognized to be the most drug resistant type of epilepsy, and HS is the most common pathological substrate identified in pharmacoresistant temporal lobe epilepsy. The condition is characterized by relatively well-defined clinical, electrographic, radiologic, and pathologic changes. Despite attempts in finding genetic variants associated with epilepsies by genome-wide association studies on European and Chinese subjects by our team and collaborators, limited common variants reached genome-wide significance. Meanwhile, the causes of the pathological changes in MTLE-HS remain unknown, and no preventive intervention has been identified. Discovery of novel genetic markers could allow screening patients with aggressive epilepsy subtypes for early surgical or pharmaceutical intervention, and ultimately lead to genetic therapies. To further explorer the contribution of new, rare variants in MTLE-HS, we plan to sequence exomes of 30 trios of probands with their unaffected parents. So far we have sequenced 9 trios, and 10 de novo mutations were identified. Among these, two de novo mutations are within genes involved in neurological functions (NLGN3 and NBEAL1) and might be involved in disease development. NLGN3 was reported to be associated with X-linked autism in a Swedish family and given the high comorbidity of autism spectrum disorders with epilepsy, this de novo mutation might contribute to MTLE-HS development.