Department of Neurology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Dongcheng District, Beijing, China.
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, China.
J Neurol. 2024 Mar;271(3):1385-1396. doi: 10.1007/s00415-023-12079-1. Epub 2023 Nov 19.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with complex genetic architecture. Emerging evidence has indicated comorbidity between ALS and autoimmune conditions, suggesting a potential shared genetic basis. The objective of this study is to assess the prognostic value of systematic screening for rare deleterious mutations in genes associated with ALS and aberrant inflammatory responses.
A discovery cohort of 494 patients and a validation cohort of 69 patients were analyzed in this study, with population-matched healthy subjects (n = 4961) served as controls. Whole exome sequencing (WES) was performed to identify rare deleterious variants in 50 ALS genes and 1177 genes associated with abnormal inflammatory responses. Genotype-phenotype correlation was assessed, and an integrative prognostic model incorporating genetic and clinical factors was constructed.
In the discovery cohort, 8.1% of patients carried confirmed ALS variants, and an additional 15.2% of patients carried novel ALS variants. Gene burden analysis revealed 303 immune-implicated genes with enriched rare variants, and 13.4% of patients harbored rare deleterious variants in these genes. Patients with ALS variants exhibited a more rapid disease progression (HR 2.87 [95% CI 2.03-4.07], p < 0.0001), while no significant effect was observed for immune-implicated variants. The nomogram model incorporating genetic and clinical information demonstrated improved accuracy in predicting disease outcomes (C-index, 0.749).
Our findings enhance the comprehension of the genetic basis of ALS within the Chinese population. It also appears that rare deleterious mutations occurring in immune-implicated genes exert minimal influence on the clinical trajectories of ALS patients.
肌萎缩侧索硬化症（ALS）是一种具有复杂遗传结构的神经退行性疾病。新出现的证据表明，ALS 与自身免疫性疾病之间存在共病，表明其具有潜在的共同遗传基础。本研究旨在评估系统筛查与 ALS 和异常炎症反应相关的罕见有害基因突变对预后的影响。
本研究分析了一个包含 494 例患者的发现队列和一个包含 69 例患者的验证队列，采用与人群相匹配的健康个体（n=4961）作为对照。进行全外显子组测序（WES），以鉴定 50 个 ALS 基因和 1177 个与异常炎症反应相关的基因中的罕见有害变异。评估基因型-表型相关性，并构建纳入遗传和临床因素的综合预后模型。
在发现队列中，8.1%的患者携带确诊的 ALS 变异，另有 15.2%的患者携带新的 ALS 变异。基因负担分析显示 303 个与免疫相关的基因中存在富集的罕见变异，13.4%的患者携带这些基因中的罕见有害变异。携带 ALS 变异的患者疾病进展更快（HR 2.87[95%CI 2.03-4.07]，p<0.0001），而免疫相关变异对疾病结局无显著影响。纳入遗传和临床信息的列线图模型显示，预测疾病结局的准确性有所提高（C 指数，0.749）。
本研究结果增强了对中国人群中 ALS 遗传基础的理解。此外，发生在与免疫相关基因中的罕见有害突变对 ALS 患者的临床病程影响很小。
