Combined Impact of CHCHD10 p.Gly66Val and Three other variants Suggests Oligogenic Contributions to ALS

Yiying Wang ¹ Yuxin Mi ² Hui Wang ¹ Jingsi Jiang ¹ Le Mao ¹ Yanxi Heng ¹ Xiaogang Li ³ Min Deng ^4*

• ¹ Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
• ² University of Science and Technology Beijing, Beijing, Beijing Municipality, China
• ³ Department of Neurology, Peking University Third Hospital, Beijing, China
• ⁴ Peking University Third Hospital, Haidian, China

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 CHCHD10 p.Gly66Val variant, along with three additional variants: UNC13A p.Leu1034Val, SUSD1 p.Trp704Ser, and SQSTM1 p.His359del. Variants in CHCHD10 have been found in patients with ALS and other neurodegenerative diseases with significant clinical variability, but the combinatorial effect of variants in CHCHD10 and other ALS-related genes have not been fully studied. Our findings suggest that the combined impact of these four variants contributes to the clinical presentation of ALS in this patient, distinguishing it from other, less severe neuromuscular disorders associated with CHCHD10 mutations. This patient exhibited a slow disease progression and a prolonged survival duration, in line with features of ALS patients with CHCHD10 variants. This implies that the CHCHD10 p.Gly66Val variant may play a predominant role in shaping the patient's phenotype, while the other three variants may primarily contribute to the occurrence of ALS.Overall, our study further supports the oligogenic pathogenic basis of ALS and offers new insights into understanding the intricate clinical presentations associated with CHCHD10 variants.