Clinical implications of variants of uncertain significance identified by multi-gene panel analysis in Korean patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) involves complex genetic contributions, leading to an increase in genetic screening in clinical practice. However, interpreting clinical relevance of variants of uncertain significance (VUS) and providing effective counseling remain challenging. This study aimed to evaluate the clinical relevance of VUS in Korean patients with ALS through comprehensive multi-gene panel analysis. We retrospectively analyzed genetic data from 379 ALS patients tested between January 2018 and December 2023. The multi-gene panel was expanded from 26 genes (2018–2021) to 44 genes (2022–2023). VUS were classified into high (VH) or low (VL) probability of pathogenicity based on 28 American College of Medical Genetics and Genomics criteria. Clinically actionable variants were defined as pathogenic, likely pathogenic (P/LP), or VH variants. Sixteen P/LP variants and 135 VUS were identified. While P/LP variant rates were comparable between the two panels (~ 4%), VUS were twice as high with the 44-gene panel. VH and clinically actionable variants were most prevalent in patients with onset before the age 40, with their proportions decreasing with age, whereas VL variants showed no age-related feature. The gene panel expansion had little impact on detecting clinically actionable variants in patients with onset age under 40 years (30% vs. 32%, p = 0.76), but increased the detection rate in those over 40 years (11% vs. 22%, p = 0.01). This study revealed onset age-dependent clinical implications of VUS and the utility of expanded multi-gene panel to improve the detection of clinically actionable variants particularly in late-onset patients.