Article Text
Abstract
Objectives To analyse the prevalence of pathogenic variants in DEPDC5, NPRL2 and NPRL3 that 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.
Methods Clinical 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.
Results Two novel frameshift variants and one recurrent nonsense variant were detected in DEPDC5, 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 in NPRL2 and NPRL3 did not segregate with epilepsy in families, respectively. Epileptic phenotypes of 21 patients with DEPDC5 variants 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 affected DEPDC5 expression. These loss-of-function (LoF) variants affected the DEPDC5-dependent inhibition of mTOR.
Conclusions Patients carrying DEPDC5-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.
- genetics
- epilepsy
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. All data from this study are stored in the epilepsy registration system of Peking Union Medical College Hospital. Anonymised data will be shared by request from any qualified investigator.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. All data from this study are stored in the epilepsy registration system of Peking Union Medical College Hospital. Anonymised data will be shared by request from any qualified investigator.
Footnotes
KY and XL contributed equally.
Contributors KY and XL performed the genetic experiments. KY and XL analysed the data and prepared the manuscript and figures. MW, ZY, YY, QLu and QD recruited and evaluated the patients. XZ supervised the study. QLiu and MW designed the experiments. QLiu supervised the study, assisted in editing the manuscript, and is the guarantor of the study.
Funding The study was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-034, 2021-I2M-1-018, 2022-I2M-JB-004), National Key research and Development Program of China (2022YFC2703900, 2022YFC2503804), National Natural Science Foundation of China (81971293, 81788101), National High Level Hospital Clinical Research Funding (2022-PUMCH-A-167), Capital Medical University Scientific Research Cultivation Fund (Natural) (1200020190), and Beijing Scientific Research Cultivation Plan for Health Development of Haidian District (HP2021-03-50801).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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