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

Objective: SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS. Methods: We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40 years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance. Results: We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels. Interpretation: Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients.