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Since 1993, more than 20 genes have been found to be implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS).1 Recent studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in ALS in Caucasian populations; these genes are considered major ALS-related genes.2–6 However, the genetic patterns of ALS in mainland China remain obscure. Therefore, we screened mutations in the major ALS genes in a large cohort of patients with ALS from mainland China. We also compared our results with those reported by previous population-based studies to assess the disease heterogeneity across populations.
The study enrolled 20 familial ALS (FALS) index cases, 324 patients with sporadic ALS (SALS) and 355 control subjects from Peking Union Medical College Hospital, between July 2011 and June 2012. The clinical characteristics of the patients with ALS were summarised in online supplementary table S1. All patients and control subjects were screened for mutations in SOD1, FUS, TARDBP, ANG, VCP and PFN1 genes, as well as for the presence of the GGGGCC expansions in the C9orf72 gene. An extensive review of the literature was also performed to determine the mutation frequencies of major ALS-related genes in mainland China. Full methods, materials, primers and amplification conditions for genetic sequencing are summarised in online supplementary table S2. The burden of mutations across SOD1, ANG, TARDBP, FUS and C9orf72 within mainland Chinese was compared to that within Caucasian populations using allele count-based Fisher exact tests.
Genetic screening showed that 20 patients (35.0% of FALS, 4.0% of SALS, 5.8% of combined) carried a variant of the genes screened (SOD1 8, FUS 8, TARDBP 3, ANG 1) (see online supplementary tables S3 and S4). All mutations have been listed in the ALSoD database.1 No mutations in VCP, C9orf72 or PFN1 were detected. No mutations were detected in control subjects. The clinical characteristics of patients with mutations are summarised in online supplementary table S3.
The literature review identified 10 studies that reported mutations in any of the SOD1, FUS, TARDBP, C9orf72 and ANG genes in mainland Chinese patients with ALS. Combining results from all the previous studies in mainland China including our present study, mutation rates of major ALS-related genes were 40.2% in FALS (SOD1 27.9%, FUS 7.1%, TARDBP 3.0%, C9orf72 2.2%) and 4.4% in SALS (FUS 1.9%, SOD1 1.3%, TARDBP 0.5%, C9orf72 0.4%, ANG 0.3%) (see online supplementary table S4).
Comparing the frequencies of mutations in major ALS genes among mainland Chinese patients with those reported by studies in Caucasian populations,2–6 a statistically significant difference was identified (combined p=0.01, table 1). The C9orf72 expansions were significantly more common among Caucasian patients (6.22% vs 0%, p=1.97×10−6), whereas the frequency of FUS mutations was more common among mainland Chinese patients (2.32% vs 0.65%; p=6.8×10−3). The frequencies of SOD1, ANG and TARDBP mutations were similar (all p>0.05) (table 1).
Our study showed that the mutation frequencies of major ALS-related genes were 40.2% in FALS (SOD1 27.9%, FUS 7.1%, TARDBP 3.0%, C9orf72 2.2%) and 4.4% in SALS (FUS 1.9%, SOD1 1.3%, TARDBP 0.5%, C9orf72 0.4%, ANG 0.3%) in mainland China. Significant differences were observed in the frequencies of mutations in major ALS genes between mainland Chinese and Caucasian populations (p=0.01), supporting a correlation between genetic susceptibility and origin of population.
In Caucasian populations, the most frequently detected mutations in patients with ALS were the C9orf72 repeat expansions (FALS: 18.3–52.1%, SALS: 1.9–6.1%).2–6 Our meta-analysis showed that in mainland China, C9orf72 was the fourth mostly common ALS-related gene (FALS: 2.2%, SALS: 0.3%) (see online supplementary table S4), with a mutation frequency similar to results from Japan,7 but much lower than in Caucasians.2–6 Formal comparison showed that the C9orf72 expansion was significantly more common among Caucasian patients than in mainland Chinese patients (p=1.97×10−6). All patients with a repeat expansion had a common 20-single nucleotide polymorphism consensus risk haplotype, suggesting a common founder effect that spread from Europe to East Asia in human migration history.7 It is interesting that the C9orf72 repeat expansion was relatively higher in Taiwanese patients with ALS (FALS: 16.7%; SALS: 1.5%), which might be due to the population admixture during colonial Dutch and Spanish rule in Taiwan during the 17th century.8
The FUS gene is supposed to be the fourth most commonly mutated gene after C9orf72, SOD1 and TARDBP gene in Caucasians (0%–6.2% in FALS and 0%–0.9% in SALS).2–6 Our meta-analysis showed that, in mainland China, FUS is the most commonly mutated gene in SALS (1.9%) and the second most commonly mutated gene (7.1%) in FALS, with a frequency similar to that of the Taiwanese population (FALS: 6.7%, SALS: 1.5%),8 slightly lower than results from Korea (FALS: 11.1%; SALS: 1.2%),9 but much higher than those of Caucasians.2–6 Population comparisons showed that FUS mutations were significantly more common among mainland Chinese patients than those among Caucasian populations (p=6.8×10−3). The high frequency of FUS mutations in FALS and SALS in mainland China is another genetic feature distinct from Caucasians.
In mainland Chinese, SOD1 mutations are the most common in FALS (27.9%) and the second most common in SALS (1.3%), and the TARDBP gene is the third most commonly mutated gene in FALS and SALS (3.0% in FALS and 0.5% in SALS) (see online supplementary table S4). SOD1 mutations are the second most common and TARDBP mutations the third most common in Caucasian patients with ALS.2–6 The frequencies of SOD1 and TARDBP mutations were similar between mainland Chinese and Caucasian populations (all p>0.05) (table 1).
There are several limitations in this study. First, there were few studies that sequenced the FUS mutations in patients with ALS aside from ours. Second, the patients included in our cohort and others studied in mainland China were those referred to ALS clinics. Such referral cohorts might be biased towards the inclusion of younger patients who are more likely to carry a genetic mutation. Third, it has been shown that inheritance of high-penetrance variants can occur in the absence of a detectable family history.10 The one child family policy in China might also increase the proportion of highly penetrant ALS mutations in FALS, and many apparent SALS might in fact be FALS. Despite the limitations, our results could be a realistic reflection of the distribution of ALS mutations in mainland China.
In conclusion, our study demonstrated that mutations in major ALS-related genes could explain 40.2% of FALS and 4.4% of SALS in mainland China. The genetic architecture of ALS in mainland Chinese is distinct from that in Caucasian populations, with SOD1 and FUS being the most frequently mutated ALS-related genes, and C9orf72 repeat expansions being less common. Our results highlight the importance of genetic heterogeneity across populations and are valuable for genetic counselling of Chinese origin patients with ALS.
The authors thank the patients and their families, as well as the healthy control subjects, for their cooperation in this study, and the anonymous reviewers for their helpful suggestions on quality improvement of our report.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Data supplement 1 - Online supplement
Contributors Z-YZ and L-YC contributed to scientific planning and direction, data analysis, and writing the manuscript. Z-YZ, M-SL, X-GL and L-YC contributed to patient selection, preliminary genetic screening and record collection. Z-YZ contributed to sequencing and genotyping. All the authors reviewed and approved the manuscript.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethical approval was obtained from the ethics committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences.
Provenance and peer review Not commissioned; externally peer reviewed.