VEXAS Syndrome Beyond UBA1: Genetic Architecture and the Role of Co-Occurring Somatic Mutations-A Focused Review

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset inflammatory disorder caused by acquired mutations in UBA1, the gene encoding the primary ubiquitin-activating enzyme. The recognition of VEXAS has transformed the current understanding of autoinflammatory disease by demonstrating that somatic alterations arising within hematopoietic stem cells can precipitate severe, multisystem inflammation in later life. While pathogenic UBA1 variants are essential to disease pathogenesis, many affected individuals also harbor additional somatic mutations associated with clonal hematopoiesis, most commonly involving DNMT3A and TET2. These concurrent mutations may contribute to clonal architecture; however, their independent impact on inflammatory phenotype and hematologic manifestations remains incompletely defined. Emerging evidence suggests that co-occurring clonal hematopoiesis mutations may be independently associated with poorer overall survival, though their causal role remains unestablished. This review examines the evolving genetic framework of VEXAS syndrome, emphasizing UBA1 as the obligate driver mutation while reviewing current evidence regarding non-Met41 UBA1 variants and co-occurring somatic mutations.