Abstracts

Rationale: Although epilepsy surgery is the most effective treatment for drug-resistant mesial temporal lobe epilepsy (MTLE), 20-50% of ideal candidates for MTLE surgery continue to have seizures post-operatively. The reasons for these surgical failures are not well understood, and a role of genetic factors has been hypothesised. This study investigated the influence of ultra-rare genetic variation on seizure outcome after MTLE surgery. Methods: This case-control study examined whole exome sequencing (WES) data from patients who underwent surgery for drug-resistant unilateral MTLE with MRI evidence of hippocampal sclerosis or a normal MRI, and who had ≥2 years of post-operative follow-up. Unilateral MTLE was defined by concordant pre-surgical investigations. Only patients at the extremes of seizure outcome were included, i.e. seizure-freedom (favourable outcome) or uncontrolled seizures since surgery (unfavourable outcome). Patients were recruited across nine epilepsy surgery centres (five in North America, two in Europe, and two in Australia) through the EPIGEN collaboration, and their exomes were sequenced at the Institute for Genomic Medicine (IGM) at Columbia University. Exomes of controls without epilepsy were also included, sequenced at IGM for unrelated studies. Ultra-rare deleterious variants comprised damaging missense (predicted by Polyphen-2 HumDiv), splice-disrupting, stop-gained, and frameshift variants, which had a minor allele frequency in the combined case and control cohorts of <0.0005 and were not observed in population datasets (EVS, ExAC, gnomAD and discoverEHR). Results: We compared WES data from 150 patients with favourable outcome, 49 patients with unfavourable outcome, and 8,820 controls. The proportion of individuals with ultra-rare deleterious variants in dominant human epilepsy genes (primary endpoint) did not differ significantly across the three groups: 7.3% among patients with favourable outcome, 8.2% among patients with unfavourable outcome, and 5.2% among controls (Fisher’s Exact test, p=0.32). Compared to controls, neither patients with favourable outcome nor those with unfavourable outcome carried an excess of ultra-rare deleterious variants in genes intolerant to loss-of-function or in genes associated with epilepsy. Neither patient group exhibited an excess of ultra-rare deleterious variants in genes associated with specific epilepsy-related targets, including voltage-gated cation channel genes, inhibitory GABA-A receptor genes or mTOR pathway genes. Conclusions: This study indicates that, compared to patients who become seizure-free after MTLE surgery, surgical failures are not enriched for individuals with ultra-rare deleterious variation in established epilepsy genes or highly constrained genes. Overall, our results suggest that ultra-rare genetic variation does not play a major role in determining the poor outcome of MTLE surgery. Funding: No funding