Shen Dongchao, Yang Xunzhe, He Di, Zhang Kang, Liu Shuangwu, Sun Xiaohan, Li Jinyue, Cai Zhengyi, Liu Mingsheng, Zhang Xue, Liu Qing, Cui Liying
Department of Neurology, Peking Union Medical College Hospital, Beijing, China.
McKusick-Zhang Center for Genetic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Aging Neurosci. 2025 May 21;17:1584541. doi: 10.3389/fnagi.2025.1584541. eCollection 2025.
Rare variants have been implicated in amyotrophic lateral sclerosis (ALS), but their prevalence and clinical significance remain poorly understood, particularly across different ethnic populations.
We performed genetic screening of in 1627 Chinese ALS patients using whole-exome sequencing. A systematic review and meta-analysis of the published literature were conducted to evaluate the global frequency of variants and their clinical correlations.
We identified 14 missense variants and 6 splice region variants in 23 unrelated patients, with four variants classified as damaging (p.R782P, p.M799T, p.R847C, and p.S997R). The splice variant c.1490-3C > T, associated with a 50% reduction in mRNA expression, was maternally inherited by a male ALS patient, while its presence in his asymptomatic mother suggests the involvement of potential genetic modifiers. variant carriers demonstrated earlier disease onset compared to non-carriers (46.9 ± 10.3 vs. 52.6 ± 11.2 years; = 0.015), though survival duration remained comparable. Meta-analysis revealed a pooled variant frequency of 0.83% (95% CI, 0.56-1.10%) in ALS patients globally, with notable ethnic differences (1.36% in Chinese, 0.66% in European, and 1.44% in American populations).
Our findings establish the prevalence of variants in ALS across different populations and suggest their potential role as disease modifiers, particularly affecting the age of onset. The ethnic variation in mutation frequency highlights the importance of population-specific genetic screening strategies in ALS.
罕见变异已被认为与肌萎缩侧索硬化症(ALS)有关,但其患病率和临床意义仍知之甚少,尤其是在不同种族人群中。
我们对1627例中国ALS患者进行了全外显子组测序的基因筛查。对已发表文献进行系统评价和荟萃分析,以评估变异的全球频率及其临床相关性。
我们在23例无亲缘关系的患者中鉴定出14个错义变异和6个剪接区域变异,其中4个变异被归类为有害变异(p.R782P、p.M799T、p.R847C和p.S997R)。剪接变异c.1490-3C>T与mRNA表达降低50%相关,由一名男性ALS患者母系遗传,而其无症状母亲携带该变异表明可能存在遗传修饰因子。与非携带者相比,变异携带者的疾病发病年龄更早(46.9±10.3岁对52.6±11.2岁;P=0.015),尽管生存时间相当。荟萃分析显示,全球ALS患者中变异的合并频率为0.83%(95%CI,0.56-1.10%),存在显著的种族差异(中国人中为1.36%,欧洲人中为0.66%,美国人中为1.44%)。
我们的研究结果确定了不同人群中ALS变异的患病率,并表明它们作为疾病修饰因子的潜在作用,特别是对发病年龄的影响。突变频率的种族差异凸显了针对特定人群的ALS基因筛查策略的重要性。