High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in ALS

SOD1 is the second most mutated gene in European amyotrophic lateral sclerosis (ALS) patients, after C9orf72 expansion. Given the recent authorisation of SOD1-directed antisense oligonucleotide for use in SOD1-ALS patients, prompt screening for SOD1 mutations in 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, with important implications for early therapeutic intervention in presymptomatic carriers.

We analysed variants in the SOD1 gene within exome sequencing data from 470,000 individuals over 40 years old at the time of recruitment. We evaluated their pathogenic role using referenced databases and according to ACMG guidelines. Leveraging the carrier frequency in UKB and age at onset distribution data, we estimated the disease prevalence of SOD1 -ALS.

We identified 122 individuals with monoallelic SOD1 coding variants. 93.4% of them were asymptomatic at enrollment. In addition, the low penetrance disease allele p.Asp91Ala was observed in heterozygosis in 535 subjects, while it was never found in homozygosis. Based on this data, the expected number of people developing SOD1-ALS in the UK population, excluding the p.Asp91Ala allele, is 1.1:100,000, four times higher than the prevalence derived from clinical data.

Incomplete and age-related penetrance and heterogeneous phenotypic expression likely account for the reduced number of symptomatic patients identified. Our findings highlight the need for systematic genetic screening in the general population, which could dramatically expand the pool of individuals who might benefit from novel molecular-silencing therapies presymptomatically. Given the existence of a therapeutic option, an in-depth follow-up of these subjects is highly recommended.