The landscape of epilepsy-related GATOR1 variants

Genet Med. 2019 Feb;21(2):398-408. doi: 10.1038/s41436-018-0060-2. Epub 2018 Aug 10.


Purpose: To 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 METHODS: We 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.

Results: The 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.

Conclusion: Our 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.

Keywords: DEPDC5; Focal cortical dysplasia; Genetic focal epilepsy; SUDEP; mTORC1 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Brugada Syndrome / genetics
  • Brugada Syndrome / mortality
  • Brugada Syndrome / physiopathology
  • Child
  • Child, Preschool
  • DNA Copy Number Variations / genetics
  • Epilepsy / complications
  • Epilepsy / epidemiology
  • Epilepsy / genetics*
  • Epilepsy / physiopathology
  • Female
  • GTPase-Activating Proteins / genetics*
  • Genetic Predisposition to Disease
  • Humans
  • INDEL Mutation / genetics
  • Infant
  • Infant, Newborn
  • Loss of Function Mutation / genetics
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Multiprotein Complexes / genetics
  • Pedigree
  • Repressor Proteins / genetics*
  • Seizures / complications
  • Seizures / epidemiology
  • Seizures / genetics
  • Seizures / physiopathology
  • Signal Transduction / genetics
  • Tumor Suppressor Proteins / genetics*


  • DEPDC5 protein, human
  • GTPase-Activating Proteins
  • Multiprotein Complexes
  • NPRL2 protein, human
  • NPRL3 protein, human
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • Mechanistic Target of Rapamycin Complex 1