Genomic ascertainment for UBA1 variants and VEXAS syndrome: a population-based study

ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. This study used a genomic ascertainment approach to overcome these limitations and better define UBA1-related disease. ObjectiveDetermine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting and ParticipantsThis cohort study evaluated UBA1 variants in exome data from 163,096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record (EHR) data up to January 1st, 2022. Main outcomes and measuresPrevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other symptoms in individuals with somatic UBA1 variation; structured and manual review of EHR; review of bone marrow biopsies; survival in carriers of somatic UBA1 variation. ResultsIn a retrospective study of 163,096 participants (mean age 52.8 years; 94% of European ancestry, 61% female), 11 individuals harbored somatic, known pathogenic UBA1 variants, with 100% having clinical manifestations consistent with VEXAS syndrome. We found a previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) in a symptomatic patient. Disease-causing UBA1 variants were found in [~]1 in 14,000 unrelated individuals, and [~]1 in 4,000 men >50 years old. A disease-causing UBA1 variant confers a [~] 6.6 higher probability of mortality vs. age-, sex-, and BMI-matched non-carriers. The majority (7, 58%) of individuals did not meet criteria for rheumatologic and hematologic diagnoses previously associated with VEXAS syndrome, however all individuals had anemia (mean 7.8 g/dL, median 7.5g/dL), mostly macrocytic (91%) with concomitant thrombocytopenia (91%). Finally, we identified a pathogenic variant in one male prior to onset of VEXAS-related signs or symptoms and two females had disease with heterozygous variants. Conclusions and relevanceThis cohort study showed that the prevalence, penetrance, and expressivity of pathogenic UBA1 variants were higher than expected. More expansive UBA1 testing will lead to molecular diagnoses and improved treatment for patients.