RT Journal Article
SR Electronic
T1 Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 840
OP 849
DO 10.1136/jmedgenet-2021-107965
VO 59
IS 9
A1 Yong-Ping Chen
A1 Shi-Hui Yu
A1 Qian-Qian Wei
A1 Bei Cao
A1 Xiao-Jing Gu
A1 Xue-Ping Chen
A1 Wei Song
A1 Bi Zhao
A1 Ying Wu
A1 Ming-Ming Sun
A1 Fei-Fei Liu
A1 Yan-Bing Hou
A1 Ru-Wei Ou
A1 Ling-Yu Zhang
A1 Kun-Cheng Liu
A1 Jun-Yu Lin
A1 Xin-Ran Xu
A1 Chun-Yu Li
A1 Jing Yang
A1 Zheng Jiang
A1 Jiao Liu
A1 Yang-Fan Cheng
A1 Yi Xiao
A1 Ke Chen
A1 Fei Feng
A1 Ying-Ying Cai
A1 Shi-Rong Li
A1 Tao Hu
A1 Xiao-Qin Yuan
A1 Xiao-Yan Guo
A1 Hui Liu
A1 Qing Han
A1 Qing-Qing Zhou
A1 Na Shao
A1 Jian-Peng Li
A1 Ping-Lei Pan
A1 Sha Ma
A1 Hui-Fang Shang
YR 2022
UL http://jmg.bmj.com/content/59/9/840.abstract
AB 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.All data relevant to the study are included in the article or uploaded as supplementary information.