Mapping VEXAS-associated and rare UBA1 variants in the United Kingdom: Insights from patient cohorts and the general population

Abstract

Somatic mutations in UBA1 are linked to VEXAS syndrome, a late-onset inflammatory disorder with rheumatological and haematological features, primarily affecting elderly men. This study examines the epidemiology of VEXAS in the United Kingdom using genomic databases and patient cohorts to estimate prevalence, identify novel UBA1 variants and predict their pathogenicity. Analysing data from the UK Biobank, 100 000 Genomes Project and clinical diagnostic laboratories, we found that VEXAS prevalence in UK males over 50 is lower than in US-based cohorts. Notably, canonical (Met41) UBA1 mutations appear in ~1% of individuals with autoinflammatory disorders who have not been referred to haematology. However, among those investigated for myeloid malignancies, VEXAS is relatively common, with an estimated incidence of 1.51 per 100 000, or 171 new cases each year. We identified 47 UBA1 non-Met41 variants of uncertain significance, with several showing clonal dominance and clustering in functional domains, suggesting potential pathogenicity. Clinical presentation associated with non-Met41 variants often diverged from classical VEXAS features, underscoring the need for further studies. Our findings highlight the importance of broader screening for both canonical and non-canonical UBA1 mutations to improve understanding of VEXAS syndrome and its underlying mechanisms.