Clinical and genetic features of GATOR1 complex-associated epilepsy

Abstract

ObjectivesTo analyse the prevalence of pathogenic variants inDEPDC5,NPRL2andNPRL3that encode the GATOR1 (GTPase-activating protein towards the Rags 1) complex, a modulator in the mammalian target of rapamycin (mTOR) pathway, and to define the characteristics of GATOR1-associated epilepsy.MethodsClinical details and whole-exome sequencing data of 170 novel probands with lesional or non-lesional epilepsy were retrieved. Candidate variants in GATOR1 genes were verified by Sanger sequencing, and cosegregate analysis was performed. The pathogenicity of variants and their effect on mTOR signalling were investigated.ResultsTwo novel frameshift variants and one recurrent nonsense variant were detected inDEPDC5, with a prevalence of 1.8% (3 out of 170) in the whole cohort and 3.1% (3 out of 97) in focal epilepsies. These variants cosegregated in pedigrees with epilepsy, respectively. Rare missense variants inNPRL2andNPRL3did not segregate with epilepsy in families, respectively. Epileptic phenotypes of 21 patients withDEPDC5variants showed focal seizures with non-lesional variable foci that were predominantly sleep-related, with a median onset age of 10 years (range 1–30). Seizure outcome was variable. About 24% of patients were drug-resistant, and seizure attacks were absent in 33% of variant carriers. Of 13 patients who experienced seizures, 54% tended to resolve spontaneously. Functional assessments showed that the three variants affectedDEPDC5expression. These loss-of-function (LoF) variants affected theDEPDC5-dependent inhibition of mTOR.ConclusionsPatients carryingDEPDC5-LoF variants might show a high prevalence of focal seizures with a dynamic phenotype, indicating reduced penetrance and self-resolving features. The associated epilepsy was caused by loss of inhibition of the mTOR pathway. The pathogenicity of missense variants in GATOR1 genes should be cautiously evaluated.