Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (6): 2468-2475.doi: 10.4103/NRR.NRR-D-24-00701

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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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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