Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 May 25.
doi: 10.1111/bjh.20176. Online ahead of print.

Mapping VEXAS-associated and rare UBA1 variants in the United Kingdom: Insights from patient cohorts and the general population

Ana Martinez Rodriguez  1 , Leon Chang  1 , Dorota Rowczenio  2 , Alexandra Smith  3 , Ebun Omoyinmi  2 , James A Poulter  4 , Andrew McGregor  5 , Sebastian Francis  6 , Roochi Trikha  7 , Adam Al-Hakim  1   8 , Kar Lok Kong  9 , David G Kent  10 , Helen Lachmann  2 , Austin Kulasekararaj  7 , Catherine Cargo  11 , Sinisa Savic  1   8   12
Affiliations
Free article

Mapping VEXAS-associated and rare UBA1 variants in the United Kingdom: Insights from patient cohorts and the general population

Ana Martinez Rodriguez et al. Br J Haematol. .
Free article

Abstract

Somatic mutations in UBA1 are linked to VEXAS syndrome, a late-onset inflammatory disorder with rheumatological and haematological features, primarily affecting elderly men. This study examines the epidemiology of VEXAS in the United Kingdom using genomic databases and patient cohorts to estimate prevalence, identify novel UBA1 variants and predict their pathogenicity. Analysing data from the UK Biobank, 100 000 Genomes Project and clinical diagnostic laboratories, we found that VEXAS prevalence in UK males over 50 is lower than in US-based cohorts. Notably, canonical (Met41) UBA1 mutations appear in ~1% of individuals with autoinflammatory disorders who have not been referred to haematology. However, among those investigated for myeloid malignancies, VEXAS is relatively common, with an estimated incidence of 1.51 per 100 000, or 171 new cases each year. We identified 47 UBA1 non-Met41 variants of uncertain significance, with several showing clonal dominance and clustering in functional domains, suggesting potential pathogenicity. Clinical presentation associated with non-Met41 variants often diverged from classical VEXAS features, underscoring the need for further studies. Our findings highlight the importance of broader screening for both canonical and non-canonical UBA1 mutations to improve understanding of VEXAS syndrome and its underlying mechanisms.

Keywords: MDS; UBA1; VEXAS.

PubMed Disclaimer

References

REFERENCES

    1. Ramser J, Ahearn ME, Lenski C, Yariz KO, Hellebrand H, von Rhein M, et al. Rare missense and synonymous variants in UBE1 are associated with X‐linked infantile spinal muscular atrophy. Am J Hum Genet. 2008;82:188–193. https://doi.org/10.1016/j.ajhg.2007.09.009
    1. Collins JC, Magaziner SJ, English M, Hassan B, Chen X, Balanda N, et al. Shared and distinct mechanisms of UBA1 inactivation across different diseases. EMBO J. 2024;43:1919–1946. https://doi.org/10.1038/s44318‐024‐00046‐z
    1. Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, et al. Somatic mutations in UBA1 and severe adult‐onset autoinflammatory disease. N Engl J Med. 2020;383:2628–2638. https://doi.org/10.1056/NEJMoa2026834
    1. Ferrada MA, Savic S, Cardona DO, Collins JC, Alessi H, Gutierrez‐Rodrigues F, et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood. 2022;140:1496–1506. https://doi.org/10.1182/blood.2022016985
    1. Georgin‐Lavialle S, Terrier B, Guedon AF, Heiblig M, Comont T, Lazaro E, et al. Further characterization of clinical and laboratory features in VEXAS syndrome: large‐scale analysis of a multicentre case series of 116 French patients. Br J Dermatol. 2022;186:564–574. https://doi.org/10.1111/bjd.20805