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

Abstract

BackgroundA 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.MethodsA 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.Findings155 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.ConclusionsOur 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.

The mutation spectrum of Parkinson‐disease‐related genes in early‐onset Parkinson's disease in ethnic Chinese

“…In addition, as described in our previous studies [14, 19], demographic data, clinical data, and assessment of motor severity, cognitive function, depression and anxiety were collected. A total of 1866 Chinese controls, including 998 males and 868 females, whose mean age was 57.9 ± 9.0 years and who had neither a medical nor family history of neurodegenerative disorders, were used as the control group in our genetic studies for neurodegenerative diseases [20]. This study was approved by the ethics committee of West China Hospital, Sichuan University.…”

Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

“…In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients, and two (4.3%) rare missense variants were identified among the 46 fALS cases, where familial cases had a relatively higher variation frequency. This phenomenon could be due to the following: firstly, as found in our previous study, familial cases are much more likely be caused by genetic causes than sporadic cases (40.6% in fALS vs. 8.6% in sALS) ( Chen et al, 2021 ); secondly, the sample size of familial cases was relatively small. It is interesting to note that, besides the classical phenotype of ALS and ALS with cognitive impairment, our current study found one familial case presenting with a comorbidity of ALS and PSP who had rapid progression and short survival.…”

Clinical and genetic study of a Chinese family affected by both amyotrophic lateral sclerosis and autosomal dominant polycystic kidney disease

“…To date, more than 238 SOD1 mutations have been reported ( http://www.hgmd.cf.ac/uk/ ). In our previous research, we found that SOD1 is the most common causative gene, followed by FUS, TARDBP, VCP , and OPTN and that it accounts for 21.88% of fALS in Southwest China ( 15 , 16 ). Analyzing this large family indicated that the patients with ALS carried SOD1 p.H47R variant (also coded as p.H46R), which has been reported to be the most frequent variant in Chinese ALS patients with SOD1 mutations ( 17 ).…”