Oligogenic inheritance in epilepsy: A systematic exome-wide analysis

Objective: Genetic factors contribute to the majority of epilepsies, but the exact genetic cause remains unknown in most patients. Incomplete penetrance and variable expressivity are frequent, and recent studies showed a burden of deleterious variants in epilepsy genes, suggesting a role for oligogenic inheritance. Here, we investigated both monogenic and oligogenic inheritance in a large cohort of patients with epilepsy. Methods: We used exome data of 422 patients and 5308 nonepileptic individuals generated by the Epi25 Collaborative project. First, a stepwise monogenic analysis was performed on all patients. Next, we restricted the cases and controls to samples sequenced with the same capture kit and removed ancestry outliers using a principal component analysis approach. We performed an oligogenic analysis on this set of samples using bioinformatic tools that predict the pathogenicity of variant combinations. We used two different approaches, a cohort-based approach in 240 patients and an individual approach in six severely affected patients. Results: Monogenic pathogenic variants were identified in 16 patients. Oligogenic cohort-based analysis identified 12 gene combinations significantly overrepresented in cases compared to controls. Individual-based analysis identified networks of variants in six patients. Manual curation of each of the variant combinations and phenotypes could not definitively confirm pathogenicity, and all combinations were finally discarded. Significance: Although we could not identify any definite oligogenic combination, our study shows that individual oligogenic analysis is implementable in selected patients and represents a feasible addition to monogenic analysis.