VEXAS-Defining UBA1 Somatic Variants in 245,368 Diverse Individuals in the NIH All Of Us Cohort

Objective: Somatic variants in UBA1 cause VEXAS, a recently described, systemic autoinflammatory disease. Research on VEXAS has largely focused on highly symptomatic patients. We sought to determine the prevalence of canonical, VEXAS-associated somatic variants and their disease penetrance in a diverse, unselected population. Methods: We analyzed clinical-grade whole genome sequencing data from 245,368 participants in the All of Us Research Program. We compared persons carrying a canonical VEXAS-associated somatic variant to age, sex, and ancestry matched controls across the domains of diagnoses, medications, and laboratory values. Results: 74 participants were identified who carry one VEXAS-defining somatic variant, UBA1 c.121A>C, p.Met41Leu. The variant allele fraction ranged from 4.5% to 33%. No other canonical VEXAS-associated variants were identified. Of the 74 carriers, 62 (84%) were women, 20 (27%) were African American, and 14 (19%) were American Admixed/Latino. There was no statistically significant association between case/control status and any VEXAS-associated diagnosis code, medication prescription, or laboratory value. Conclusion: We report the largest cohort to date of persons with the VEXAS-associated p.Met41Leu somatic variant. This cohort differed substantially from reported cohorts of patients with clinical VEXAS, having a higher proportion of persons who were young, female, and of diverse ancestry. Variant allele fractions were lower than reported in clinical VEXAS cohorts, and bioinformatic analysis detected no clinical manifestations of VEXAS. Thus, the UBA1 p.Met41Leu somatic variant displayed incomplete penetrance for VEXAS. Further study is needed to determine the natural history of VEXAS-associated somatic variants in the predisease phase.