Abstract
PurposeTo define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway MethodsWe analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. ResultsThe GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. ConclusionOur data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
Highlights
Genes encoding components of the amino acid–sensitive branch of the mechanistic target of rapamycinsignaling pathway were first implicated in familial focal epilepsies in 2013.1,2 DEPDC5 (DEP domain containing protein 5), together with NPRL2 and NPRL3 form the GATOR1 (GAP activity towards rags complex 1) complex, a repressor of the mechanistic target of rapamycin complex 1 pathway.[3]
The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and Sudden unexpected death in epilepsy (SUDEP)
Signaling pathway were first implicated in familial focal epilepsies in 2013.1,2 DEPDC5 (DEP domain containing protein 5), together with NPRL2 and NPRL3 form the GATOR1
Summary
Signaling pathway were first implicated in familial focal epilepsies in 2013.1,2 DEPDC5 (DEP domain containing protein 5), together with NPRL2 and NPRL3 (nitrogen permease regulator-like 2 and 3) form the GATOR1 (GAP activity towards rags complex 1) complex, a repressor of the mechanistic target of rapamycin complex 1 (mTORC1) pathway.[3] Heterozygous germline variants in the GATOR1encoding genes (DEPDC5, NPRL2, and NPRL3) are found in up to 37% of familial focal epilepsies,[4] as well as in some cases with Rolandic epilepsy[5] or infantile spasms.[6] Mendelian focal epilepsies caused by variants in GATOR1 genes encompass familial focal epilepsy with variable foci (FFEVF, MIM 604364),[1,2] autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE, recently renamed sleep-related hypermotor epilepsy [SHE]),[7] and familial temporal lobe epilepsy.[2]. We further delineate the GATOR1 phenotype spectrum and provide an updated and critical review of all novel and previously reported GATOR1 epilepsy-related variants, with new guidance for their clinical interpretation
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