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Original research
Clinical and genetic features of GATOR1 complex-associated epilepsy
  1. Kaili Yin1,2,
  2. Xingxing Lei1,2,
  3. Zhaofen Yan3,4,
  4. Yujiao Yang3,4,
  5. Qinqin Deng3,4,
  6. Qiang Lu2,
  7. Xue Zhang1,5,
  8. Mengyang Wang3,4,
  9. Qing Liu2,5
  1. 1McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, Beijing, China
  2. 2Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
  3. 3Epilepsy Center and Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Haidian District, Beijing, China
  4. 4Key Laboratory of Epilepsy, Beijing Institute for Brain Disorders, 50 Xiang-shan-xi-song, Beijing, China
  5. 5Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
  1. Correspondence to Dr Qing Liu, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China; drliuqing{at}126.com; Dr Mengyang Wang; mengyangwang{at}ccmu.edu.cn

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.

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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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.