Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Abstract

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.ObjectiveTo determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.Design, Setting, and ParticipantsThis retrospective observational 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 data from January 1, 1996, to January 1, 2022.ExposuresExome sequencing was performed.Main Outcomes and MeasuresOutcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.ResultsIn 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).Conclusions and RelevanceThis study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

VEXAS syndrome: A review of bone marrow aspirate and biopsies reporting myeloid and erythroid precursor vacuolation

“…Templé, et al recently described two cases of VEXAS syndrome in adult males with an atypical splice site mutation in UBA1 resulting in typical clinical features of VEXAS (severe autoinflammatory disease, macrocytic anemia and dysplasia) but without bone marrow vacuolation 13 . Moreover, while VEXAS syndrome is an acquired, X‐linked disease and thus occurs predominantly in men, it has also been described in women with or without monosomy X and one patient with Turner syndrome from our own center (included in the present study) 2,12,14 . The impact of UBA1 mutations in females with a 46XX karyotype requires further study 2 …”

“…13 Moreover, while VEXAS syndrome is an acquired, X-linked disease and thus occurs predominantly in men, it has also been described in women with or without monosomy X and one patient with Turner syndrome from our own center (included in the present study). 2,12,14 The impact of UBA1 mutations in females with a 46XX karyotype requires further study. 2 Currently, allogeneic HSCT is the only definitive treatment for VEXAS syndrome.…”

“…In their seminal paper, Beck et al determined that all affect individuals had cytopenias as well as vacuolation of myeloid and erythroid (ME) precursors on BAMB 1 . Somatic mutations at known pathogenic UBA1 sites are seen in 0.007% of the population 2 …”

“…1 Somatic mutations at known pathogenic UBA1 sites are seen in 0.007% of the population. 2 Vacuolation of ME precursors are a dysplastic feature associated with multiple processes such as copper deficiency, acute alcohol toxicity, MDS, and AML. [3][4][5][6] Historically, certain pathognomonic morphologic features have been critical in diagnosing underlying disease pathology.…”

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

“…Some of the identified somatic variants were also on functional residues (S478, R551, N606, S621, R747), one of which is a partial loss of function site (R747). The literature and prevalence in public databases on the identified putative somatic variants are summarized in Table 2 [7,20,33,[35][36][37][38][39][40][41][42][43][44].…”