Abstracts

Rationale: Targeted next-generation sequencing and whole exome sequencing (WES), enables identification of pathogenic variants in a significant number of patients with unexplained epilepsy. A genetic diagnosis may enable more accurate counseling regarding prognosis and recurrence risk, avoid unnecessary medical investigations and change care. In this study, we report the results of WES on 151 patients with early onset epilepsy of unknown cause. Methods: WES was performed on 151 patients attending BC Children’s Hospital with a history of early onset epilepsy (= 5 years) between December 2014 - October 2016. Detailed clinical data was abstracted in a REDCap database. WES was performed on an Ion Proton™ System. Reporting was initially restricted to the sequences of 801 genes, including 565 previously implicated in epilepsy. Proband-parent trio-based WES analyses was then performed in 23 patients with no immediate genetic diagnosis. Putative causative mutations were validated by Sanger sequencing and by parental testing. Results: A definite/likely diagnosis was initially made in 37 patients (25%), which included the identification of variants in 25 known epilepsy genes. Variants were most commonly seen in SCN1A (7), KCNQ2 (3), STXBP1 (2), GABRA1 (2), DYRK1A (2) and MECP2 (2). Two recently described epilepsy genes were identified in 2 patients (HNRNPU and SLC1A2) with epileptic encephalopathies. A possible diagnosis was identified in 15 additional patients (10%) for which supporting evidence is pending, including one possible novel genetic etiology (YWHAG). Subsequent trio-based WES analyses on 23 patients with no immediate genetic diagnosis identified a definitely/likely diagnosis in 2 additional patients (SMARCA2; FGF12); and a possible diagnosis in 2 patients (PIGA; KCNQ5 (likely positive novel epilepsy gene)). In 11 additional patients, we identified a candidate gene for which supporting evidence is pending. 17 out of 39 patients (44%) had a genetic diagnosis with potential treatment implications. Conclusions: The clinical benefits of using WES in the diagnostic workup of patients with early onset epilepsy is supported by the diagnostic yield of 26% (39/151 patients) with potential treatment implications in 44% (17/39). Subsequent trio-based WES analyses in a subset of patients resulted in a mild increase in the diagnostic yield, and allowed for the identification of candidate epilepsy genes which require further investigation. Further studies measuring the impact of WES on long-term clinical outcome will be important. Funding: Canada Excellence Research Chair and Leading Edge Endowment Funds, the Rare Disease Foundation, the Grocholski Foundation, and the Alva Foundation.