Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

Autor:	Chen YP; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Yu SH; Guangzhou KingMed Diagnostics Group Co., Ltd, Guangzhou, China., Wei QQ; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Cao B; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Gu XJ; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Chen XP; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Song W; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Zhao B; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Wu Y; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Sun MM; Guangzhou KingMed Diagnostics Group Co., Ltd, Guangzhou, China., Liu FF; Guangzhou KingMed Diagnostics Group Co., Ltd, Guangzhou, China., Hou YB; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Ou RW; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Zhang LY; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Liu KC; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Lin JY; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Xu XR; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Li CY; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Yang J; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Jiang Z; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Liu J; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Cheng YF; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Xiao Y; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China., Chen K; Department of Geriatrics, The Fourth Affiliated Hospital of Sichuan University, Chengdu, China., Feng F; Department of Neurology, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, China., Cai YY; Department of Geriatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China., Li SR; Department of Neurology, Guizhou Provincial People's Hospital, Guiyang, China., Hu T; Department of Neurology, The Affiliated Hospital of Sichuan Nursing Vocational College, Chengdu, China., Yuan XQ; Department of Neurology, Mianyang Central Hospital, Mianyang, China., Guo XY; Department of Neurology, Neurological Diseases and Brain Function Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China., Liu H; Department of Neurodegenerative Disease, Hertie Institute for Clinical Brain Research, University of Tuebingen and DZNE, Tuebingen, Germany., Han Q; Department of Neurology, Ningbo First Hospital & Ningbo Hospital of Zhejiang University, Ningbo, China., Zhou QQ; Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., Shao N; Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, China., Li JP; Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, China., Pan PL; Department of Neurology, The Affiliated Yancheng Hospital, School of Medicine, Southeast University, Nanjing, China., Ma S; Department of Neurology, The First People's Hospital of Yunnan Province, Kunming, China., Shang HF; Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare disease center, West China Hospital, Sichuan University, Chengdu, China hfshang2002@126.com.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2022 Sep; Vol. 59 (9), pp. 840-849. Date of Electronic Publication: 2021 Sep 20.
DOI:	10.1136/jmedgenet-2021-107965
Abstrakt:	Background: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. Methods: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72 . Forty-one ALS-associated genes were analysed. Findings: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72 , FUS , NEK1 , TARDBP and TBK1 . By burden analysis, rare variants in SOD1 , FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. Conclusions: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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