High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.

Monoallelic pathogenic SOD1 variants → ALS with variable penetrance; antisense oligonucleotides targeting SOD1 now available

Analysis of exome data from 470,000 UK Biobank individuals over 40 years identifies 122 carriers of pathogenic SOD1 coding variants, 93.4% of whom are asymptomatic. The estimated genetic prevalence of SOD1-ALS exceeds observed clinical prevalence, suggesting significant incomplete penetrance. The low-penetrance variant p.Asp91Ala is observed in 535 subjects. These data are particularly relevant in the context of available SOD1 antisense oligonucleotides (tofersen).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

With tofersen now approved, the question of presymptomatic screening of SOD1 carriers becomes concrete. This biobank study provides essential population-level prevalence data to size a potential screening program. Incomplete penetrance — and its variability across variants — remains the main challenge for presymptomatic genetic counseling.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Publication status: 1/1 → Total: 7/10