An estimate of the prevalence and clinical manifestations of UBA1 variants associated with vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome within a single regional health care system in the US were assessed in a retrospective observational study published in JAMA.
VEXAS syndrome is characterized by rheumatologic and hematologic features caused by somatic variants in UBA1, with pathogenic variants being associated with a wide spectrum of clinical manifestations. Knowledge of the prevalence, penetrance, and clinical characteristics of VEXAS is limited by ascertainment biases based on known phenotypes.
The researchers studied the prevalence, penetrance, and expressivity of UBA1 variants in a US health care system cohort, using a genomic ascertainment approach.
The UBA1 variants in exome data were evaluated from participants within the Geisinger MyCode Community Health Initiative, which is an integrated health system in central and northeastern Pennsylvania. All clinical phenotypes were established from Geisinger electronic health record (EHR) data between January 1996 and 2022.
Outcome measures included the prevalence of somatic UBA1 variation; the presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of EHR data; review of laboratory data; bone marrow biopsy analysis; and in vitro enzymatic assays.
Results of the study showed that among 163,096 participants (61% women; mean age, 52.8 years; 94% White), 11 (9 men) had somatic variants at known pathogenic UBA1 positions, with all of them exhibiting clinical manifestations consistent with VEXAS syndrome.
Overall, 45% of the individuals with somatic variants at known pathogenic UBA1 positions did not fulfill criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome. Anemia was noted among all participants (mean hemoglobin [Hb], 7.8 g/L; median Hb, 7.5 g/dL), which was mostly macrolytic with concomitant thrombocytopenia.
Of the 11 patients, a pathogenic variant was detected in 1 male participant prior to the onset of VEXAS-related signs or symptoms; 2 women participants exhibited disease with heterozygous variants. In addition, a previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was detected in a symptomatic participant, with in vitro data confirming a catalytic defect and pathogenicity.
Overall, disease-causing UBA1 variants were detected in 1 in 13,591 unrelated individuals (95% CI, 1:7775 to 1:23,758); 1 in 4269 men older than 50 years (95% CI, 1:2319 to 1:7859); and 1 in 26,238 women older than 50 years (95% CI, 1:7196 to 1:47,669).
Study limitations included the single-center design and the unaccountability for missing data from clinical findings, treatment, or testing provided by clinicians not within the single health care system.
The study authors concluded, “Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.”
Beck DB, Bodian DL, Shah V, et al. Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population. JAMA. 2023;329(4):318-324. doi:10.1001/jama.2022.24836