Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations

Area of Science:

• Genetics
• Hematology
• Immunology

Background:

• VEXAS syndrome, a severe autoinflammatory and hematologic disorder, arises from somatic mutations in the UBA1 gene.
• Distinct clinical presentations have been observed between canonical UBA1 p.Met41 (M41) mutations and non-canonical (non-M41) mutations, but data are limited.

Purpose of the Study:

• To investigate the clinical and biological differences between canonical M41 and non-M41 UBA1 mutations in a large cohort.
• To enhance the interpretation of UBA1 variants in patients with hematologic diseases.

Main Methods:

• Screening of 29,000 individuals with hematologic diseases for UBA1 variants using 62-gene panel sequencing.
• Identification of 232 patients with likely pathogenic UBA1 mutations.
• Functional assessment of polyubiquitylation and H2A/B monoubiquitylation for tested variants.

Main Results:

• Identified 232 patients with likely disease-causing UBA1 mutations, demonstrating decreased polyubiquitylation across variants.
• Confirmed M41 mutations are predominantly associated with myelodysplastic neoplasms (MDS) and rarely tolerate co-mutations.
• Observed non-M41 mutations in diverse hematologic neoplasms, often with co-mutations, and distinct H2A/B monoubiquitylation alterations compared to M41.

Conclusions:

• M41 and non-M41 UBA1 mutations present with distinct clinical phenotypes and biological impacts.
• This study significantly improves the understanding and interpretation of UBA1 variants in VEXAS syndrome and related hematologic disorders.