NEW YORK – A team led by researchers at New York University and the National Cancer Institute has started to tally the frequency and clinical symptoms associated with pathogenic UBA1 gene variants, which cause a rare syndrome called VEXAS that is marked by rheumatologic, hematologic, dermatologic, or pulmonary features.
VEXAS, which stands for "vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic," stems from somatic UBA1 variants that arise with age in bone marrow.
In a retrospective analysis of exome sequencing data from blood for nearly 163,100 Geisinger MyCode Community Health Initiative participants with available health record data, the researchers tracked down pathogenic or likely pathogenic changes to UBA1 in 11 individuals, including nine men and two women.
"The primary objective of this study was to identify the prevalence and phenotypic spectrum of UBA1 variants in an unselected clinical cohort of participants in the MyCode Community Health Initiative at Geisinger," co-corresponding authors Douglas Stewart, a researcher with NCI's Clinical Genetics Branch, and David Beck of New York University, along with their colleagues, wrote in JAMA on Tuesday.
While only five of the individuals with high-risk somatic UBA1 variants had been diagnosed with related rheumatologic or hematologic conditions, the team noted that all 11 showed characteristic clinical manifestations of the rare syndrome, including anemia. Seven of the participants with VEXAS-linked changes in UBA1 had a history of arthritis, while four had prior rheumatologic disease diagnoses, and four individuals experienced more specific VEXAS-like symptoms.
A 12th individual who carried a variant of uncertain significance in UBA1 had VEXAS-related symptoms but had been diagnosed with another condition known as granulomatosis with polyangiitis, the researchers reported. They also unearthed rare, coding mutations in UBA1 that were classified as VUSs in two other male participants.
Although the authors cautioned that VEXAS prevalence "may be overestimated if highly suspicious variants are not validated as causal in other studies," they suggested that "reported UBA1 variant prevalence is likely underestimated due to the requirements for sequence depth to detect low-level somatic variants."
Extending from their results from the MyCode cohort, the investigators estimated that likely pathogenic or pathogenic somatic variants in UBA1 may be present in one in every 4,269 men over 50 years old and in one in 26,238 women over 50, with an overall prevalence of one in 7,931 individuals in the 50-plus age group and one in 13,591 individuals across the broader age cohort considered.
"Now that we know VEXAS syndrome is more common than many other types of rheumatologic conditions, physicians need to add this condition to their list of potential diagnoses when confronted by patients with persistent and unexplained inflammation and low blood cell counts, or anemia," Beck said in a statement.
The authors noted that "[a]dditional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum."