中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (6): 2468-2475.doi: 10.4103/NRR.NRR-D-24-00701

• 原著:退行性病与再生 • 上一篇    下一篇

中国家族性肌萎缩侧索硬化症的临床和遗传学综合结构：302个家庭的15年队列研究

  

  • 出版日期:2026-06-15 发布日期:2025-09-19

Comprehensive clinical and genetic architecture of familial amyotrophic lateral sclerosis in China: A 15-year cohort study with 302 families

Wei Zheng1, 2, 3, #, Lu Xu4, 5, #, Jinling Cai1, 2, 3, #, Jinwen Hou6 , Lu Chen1, 2, 3, Nan Zhang1, 2, 3, Siyan Zhan4, 5, 7, 8, Dongsheng Fan1, 2, 3, *, Ji He1, 2, 3, 9, 10, *   

  1. 1 Department of Neurology, Peking University Third Hospital, Beijing, China;  2 Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China;  3 Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China;  4 Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China;  5 Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China;  6 School of Basic Medical Sciences, Peking University, Beijing, China;  7 Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China;  8 Center for Intelligent Public Health, Institute for Artificial Intelligence, Peking University, Beijing, China;  9 Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China; 10Changping Laboratory, Beijing, China
  • Online:2026-06-15 Published:2025-09-19
  • Contact: Dongsheng Fan, MD, PhD, dsfan2010@aliyun.com; Ji He, PhD, h27j@hotmail.com.
  • Supported by:
    This study was supported by the Natural Science Foundation of Beijing, Nos. 7244428 (to WZ) and 7222215 (to JH); the Peking University Medicine Sailing Program for Young Scholars’ Scientific and Technological Innovation, No. BMU2023YFJHPY034 (to WZ); the National Natural Science Foundation of China, Nos. 81873784, 82071426 (to DF), and 81974197 (to JH); the Clinical Cohort Construction Program of Peking University Third Hospital, No. BYSYDL2019002 (to DF); Beijing Physician-Scientist Training Program, No. BJPSTP-2024-03 (to JH); the China Postdoctoral Science Foundation, Nos. 2022TQ0014 (to LX), 2022M720284 (to LX); and the E-Town Cooperation & Development Foundation, No. YCXJ-JZ-2023-017 (to LX).

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摘要：

在肌萎缩性脊髓侧索硬化症（ALS）的发病过程中，遗传学的重要性日益凸显。然而，目前还没有专门针对亚洲人群的家族性 ALS（fALS）临床特征和遗传谱的全面分析。本研究旨在通过一项为期 15 年的临床队列研究，全面分析中国大陆地区家族性 ALS 的临床特征和遗传谱。研究共纳入了来自 28 个省份的 302 个 ALS 家庭，时间跨度为 2008 年 1 月至 2023 年 9 月。研究人员采用基于群体的轨迹模型（GBTM）计算了修订版ALS功能评分量表（ALSFRS-R）的评分进展，并对fALS患者和其他1:4匹配的散发性ALS（sALS）患者进行了自引导内部验证。共有 244 名指数患者接受了基因筛查（SOD1、FUS、TDP43 和 C9ORF72），其中 146 名患者接受了全基因组下一代测序。基因水平负担分析用于评估 ALS 患者中罕见变异的分布情况。我们发现，动态进展较快与发病年龄较大、诊断延迟时间较短、体重指数较低、球部发病以及受影响的一级亲属较多有关。发病年龄和从发病到确诊的时间等属性对 fALS 和 sALS 临床进展轨迹的影响不相上下。ALS致病基因中的致病/可能致病（P/LP）变异降低了fALS患者的发病年龄。共有17.8%的fALS患者拥有两个或两个以上的P/LP变异体。测序内核关联测试分析表明，SOD1（P=1.3e-15）的罕见变异负担与罹患 fALS 的显著风险相关。我们通过对中国大陆临床队列长达15年的随访，最终证实了fALS的临床特征和遗传谱，有助于加深对fALS基因型与表型关系的理解。基于详细的临床和遗传信息，可以评估ALS的具体临床特征、临床预后和遗传变异，为开发针对基因型的治疗方法提供依据。

https://orcid.org/0000-0002-3129-9821 (Dongsheng Fan); https://orcid.org/0000-0002-1389-3544 (Ji He)

关键词: 家族性肌萎缩侧索硬化症, 遗传, 流行病学, 基于群体的轨迹模型, 基因水平负担分析, 中国, 致病, 基因型, 表型, 队列

Abstract: The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident. However, there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population. This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland. Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023. A groupbased trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis, as well as patients with sporadic amyotrophic lateral sclerosis (matched at a 1:4 ratio, with replacement). DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1, FUS, TDP43, and C9ORF72, of which 146 were also subjected to genome-wide next-generation sequencing. Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort. We found that rapid dynamic disease progression was associated with an older age at onset, shorter diagnostic delay, lower body mass index, bulbar onset, and ≥ 1 affected first-degree relative. Certain attributes, such as age at onset and time from onset to diagnosis, had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis. Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis. Among the patients with familial amyotrophic lateral sclerosis, 17.8% possessed ≥ 2 pathogenic/likely pathogenic variants. Sequencing kernel association test analysis showed that the SOD1 rare variant burden (P = 1.3e−15) was associated with a significant risk of familial amyotrophic lateral sclerosis. Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China, contributing to a deeper understanding of genotype–phenotype relationships in familial amyotrophic lateral sclerosis. This comprehensive evaluation of specific clinical characteristics, clinical prognosis, and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.

Key words: China, cohort, epidemiological, familial amyotrophic lateral sclerosis, gene-level burden analysis, genetic, genotype, group-based trajectory model, pathogenic, phenotype