Gap Activity TOward Rags 1 variants in Chinese people with sporadic drug-resistant focal epilepsy

Objectives: GATOR1 (Gap Activity TOward Rags 1) is composed of three different subunits, DEPDC5 (DEP domain-containing protein 5), NPRL2 (nitrogen permease regulator-like 2) and NPRL3 (nitrogen permease regulator-like 3), and variants in these three genes have mostly been reported in familial focal epilepsy. However, very few studies have been carried out on sporadic drug-resistant focal epilepsy patients. In this study, we aimed to identify the frequency of variants in DEPDC5, NPRL2 and NPRL3 in patients with sporadic drug-resistant focal epilepsy.

Materials & methods: One hundred and ninety-three Chinese people with sporadic drug-resistant focal epilepsy were enrolled in the study. Targeted sequencing of DEPDC5, NPRL2 and NPRL3 was applied at an average coverage depth of 2500×.

Results: In the 193 patients with sporadic focal epilepsy included in this study, the median age was 24.6 years with a median age at onset of 13.99 years, and 130 of these patients had identifiable structural lesions. One possibly pathogenic missense variant of DEPDC5, c.2984G>A, p.Arg995His, was found in one patient (0.52%) with hippocampal sclerosis, and one variant of unknown significance, DEPDC5 c.20A>G, p.Tyr7Cys, was found in two patients with hippocampal sclerosis (1.04%).

Conclusions: Our findings suggested that DEPDC5 might be of more importance than NPRL2 or NPRL3 in Chinese epilepsy patients with sporadic drug-resistant focal epilepsy. Future research should focus on the mechanism by which the mechanistic target of rapamycin (mTOR) is involved in epileptogenesis in sporadic epilepsy.