Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Mutations in UBA1, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients diagnosed with myelodysplastic syndromes myelodysplastic syndromes: (my-eh-lo-diss-PLASS-tik SIN-dromez) A group of disorders where the bone marrow does not work well, and the bone marrow cells fail to make enough healthy blood cells. Myelo refers to the bone marrow. Dysplastic means abnormal growth or development. People with MDS have low blood cell count for at… (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n = 12) and of unknown significance (n = 15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Patients had a median of 1 additional myeloid gene mutation mutation: Any change or alteration in a gene. A mutation may cause disease or may be a normal variation. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a mutation in the PIG-A gene of a single stem cell in the bone marrow. , often in TET2 (n = 12), DNMT3A (n = 10), ASXL1 (n = 3), or SF3B1 (n = 3). Retrospective clinical review, where possible, showed that 82% (28/34) UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for systematic screening for UBA1 in the management of MDS.