Combined impact of p.Gly66Val and three other variants suggests oligogenic contributions to ALS.

INTRODUCTION

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.

METHODS

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.

RESULTS

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.

DISCUSSION

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.