|
Title
|
|
|
|
The landscape of epilepsy-related GATOR1 variants
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| 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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Genetics in medicine. - Philadelphia, Pa.
| |
|
Publication
|
|
|
|
Philadelphia, Pa.
:
2019
| |
|
ISSN
|
|
|
|
1098-3600
1530-0366
| |
|
DOI
|
|
|
|
10.1038/S41436-018-0060-2
| |
|
Volume/pages
|
|
|
|
21
:2
(2019)
, p. 398-408
| |
|
ISI
|
|
|
|
000458017600019
| |
|
Pubmed ID
|
|
|
|
30093711
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|