Journal
GENETICS IN MEDICINE
Volume 21, Issue 2, Pages 398-408Publisher
SPRINGERNATURE
DOI: 10.1038/s41436-018-0060-2
Keywords
DEPDC5; mTORC1 pathway; Genetic focal epilepsy; Focal cortical dysplasia; SUDEP
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Funding
- European Research Council [ERC 682345]
- program Investissements d'avenir [ANR-10-IAIHU-06]
- Fondation Francaise pour la Recherche sur les Epilepsies
- National Institute for Health Research (NIHR) Biomedical Research Centres funding scheme
- Muir Maxwell Trust, United Kingdom
- Epilepsy Society, United Kingdom
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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.
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