PMID- 36604176 OWN - NLM STAT- MEDLINE DCOM- 20230912 LR - 20230912 IS - 1468-6244 (Electronic) IS - 0022-2593 (Linking) VI - 60 IP - 8 DP - 2023 Aug TI - Clinical and genetic features of GATOR1 complex-associated epilepsy. PG - 784-790 LID - 10.1136/jmg-2021-108364 [doi] AB - 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. CI - (c) Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Yin, Kaili AU - Yin K AD - McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, Beijing, China. AD - Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. FAU - Lei, Xingxing AU - Lei X AD - McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, Beijing, China. AD - Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. FAU - Yan, Zhaofen AU - Yan Z AD - Epilepsy Center and Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Haidian District, Beijing, China. AD - Key Laboratory of Epilepsy, Beijing Institute for Brain Disorders, 50 Xiang-shan-xi-song, Beijing, China. FAU - Yang, Yujiao AU - Yang Y AD - Epilepsy Center and Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Haidian District, Beijing, China. AD - Key Laboratory of Epilepsy, Beijing Institute for Brain Disorders, 50 Xiang-shan-xi-song, Beijing, China. FAU - Deng, Qinqin AU - Deng Q AD - Epilepsy Center and Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Haidian District, Beijing, China. AD - Key Laboratory of Epilepsy, Beijing Institute for Brain Disorders, 50 Xiang-shan-xi-song, Beijing, China. FAU - Lu, Qiang AU - Lu Q AD - Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. FAU - Zhang, Xue AU - Zhang X AD - McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medical Sciences, Beijing, China. AD - Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China. FAU - Wang, Mengyang AU - Wang M AD - Epilepsy Center and Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Haidian District, Beijing, China drliuqing@126.com mengyangwang@ccmu.edu.cn. AD - Key Laboratory of Epilepsy, Beijing Institute for Brain Disorders, 50 Xiang-shan-xi-song, Beijing, China. FAU - Liu, Qing AU - Liu Q AUID- ORCID: 0000-0003-0196-041X AD - Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China drliuqing@126.com mengyangwang@ccmu.edu.cn. AD - Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230105 PL - England TA - J Med Genet JT - Journal of medical genetics JID - 2985087R RN - 0 (GTPase-Activating Proteins) RN - 0 (NPRL3 protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (DEPDC5 protein, human) SB - IM MH - Humans MH - *Epilepsies, Partial/genetics MH - *Epilepsy/epidemiology/genetics MH - GTPase-Activating Proteins/genetics MH - Mutation/genetics MH - Seizures/genetics MH - Signal Transduction/genetics MH - TOR Serine-Threonine Kinases/genetics/metabolism OTO - NOTNLM OT - epilepsy OT - genetics COIS- Competing interests: None declared. EDAT- 2023/01/06 06:00 MHDA- 2023/07/24 06:43 CRDT- 2023/01/05 21:42 PHST- 2021/12/04 00:00 [received] PHST- 2022/12/12 00:00 [accepted] PHST- 2023/07/24 06:43 [medline] PHST- 2023/01/06 06:00 [pubmed] PHST- 2023/01/05 21:42 [entrez] AID - jmg-2021-108364 [pii] AID - 10.1136/jmg-2021-108364 [doi] PST - ppublish SO - J Med Genet. 2023 Aug;60(8):784-790. doi: 10.1136/jmg-2021-108364. Epub 2023 Jan 5.