Wang YiYing, Mi YuXin, Wang Hui, Jiang JingSi, Mao Le, Heng YanXi, Li XiaoGang, Deng Min
Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
Daxing Research Institute, University of Science and Technology Beijing, Beijing, China.
Front Neurol. 2025 Mar 18;16:1438207. doi: 10.3389/fneur.2025.1438207. eCollection 2025.
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Genetic factors are known to play important roles in ALS and concomitant presence of rare variants in ALS patients have been increasingly reported.
In order to explore the genetic variants in ALS patients within the context of oligogenic inheritance and to elucidate the clinical heterogeneity observed in these patients, we conducted whole-genome sequencing on 34 familial ALS (FALS) probands.
In one proband, we identified a p.Gly66Val variant, along with three additional variants: p.Leu1034Val, p.Trp704Ser, and p.His359del. This patient exhibited a slow disease progression and a prolonged survival duration, consistent with the clinical features of ALS patients with variants. This suggests that the p.Gly66Val variant may play a predominant role in shaping the patient's phenotype, while the other variants may primarily contribute to ALS occurrence.
Variants in have been found in ALS and other neurodegenerative diseases, exhibiting significant clinical variability. However, the combinatorial effect of and other ALS-related gene variants has not been fully studied. Our findings suggest that the combined impact of these four variants contributes to this patient's ALS phenotype, distinguishing it from other, less severe neuromuscular disorders associated with mutations. Overall, this study further supports the oligogenic pathogenic basis of ALS and offers new insights into understanding the intricate clinical presentations associated with variants.
肌萎缩侧索硬化症（ALS）是一种严重的神经退行性疾病，其特征是运动神经元进行性丧失和肌肉萎缩。已知遗传因素在ALS中起重要作用，并且越来越多的报道称ALS患者中存在罕见变异。
为了在寡基因遗传背景下探索ALS患者的基因变异，并阐明在这些患者中观察到的临床异质性，我们对34名家族性ALS（FALS）先证者进行了全基因组测序。
在一名先证者中，我们鉴定出一个p.Gly66Val变异，以及另外三个变异：p.Leu1034Val、p.Trp704Ser和p.His359del。该患者表现出疾病进展缓慢和生存期延长，这与携带这些变异的ALS患者的临床特征一致。这表明p.Gly66Val变异可能在塑造患者表型方面起主要作用，而其他变异可能主要促成ALS的发生。
在ALS和其他神经退行性疾病中已发现相关变异，表现出显著的临床变异性。然而，与其他ALS相关基因变异的组合效应尚未得到充分研究。我们的研究结果表明，这四个变异的综合影响促成了该患者的ALS表型，使其有别于其他与相关突变有关的不太严重的神经肌肉疾病。总体而言，本研究进一步支持了ALS的寡基因致病基础，并为理解与相关变异有关的复杂临床表现提供了新的见解。
