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. Despite attempts at finding genetic variants associated with epilepsies by genome-wide association studies on European and Chinese subjects by our team and collaborators, few common variants reached genome-wide significance. 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 de novo, rare variants in sporadic MTLE-HS, we performed whole-exome sequencing on 30 trios comprising affected probands and their unaffected parents. We have identified 27 de novo mutations, among which are 7 variants in 7 genes (BHLHE40, TACC2, ROBO4, GRASP, BAIAP2, NLGN3 and NBEAL1) which are known to be involved in neurological functions, suggesting they may be involved in epilepsy development. Among these genes, ROBO4, BAIAP2 and NLGN3 have been associated with psychiatric diseases, including autism and ADHD. Given the high comorbidity of autism spectrum disorders with epilepsy, it is plausible that these de novo mutations might contribute to MTLE-HS development. Mouse models of knockout ABL2 and GRASP also provide strong evidence for their relevance to motor neuron development. We further show an increased burden of non-synonymous variants (4:1) in MTLE-HS patients vs that expected by chance and highlight the importance of our reported de novo mutations in MTLE-HS cases.