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Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Journal Title: 
Primary Author: 
Sirenko M
Sirenko M, Bernard E, Creignou M, Domenico D, Farina A, Arango Ossa JE, Kosmider O, Hasserjian RP, Jädersten M, Germing U, Sanz GF, van de Loosdrecht AA, Gurnari C, Follo MY, Thol FR, Zamora L, Pinheiro RF, Pellagatti A, Elias HK, Haase DT, Sander B, Orna E, Zoldan K, Eder LN, Sperr WR, Thalhammer R, Ganster C, Adès L, Tobiasson M, Palomo L, Della Porta MG, Huberman KH, Fenaux P, Belickova M, Savona MR, Klimek V, Santos FPS, Boultwood J, Kotsianidis I, Santini V, Sole F, Platzbecker U, Heuser M
Original Publication Date: 
Tuesday, April 30, 2024
Bone Marrow Disease(s): 

Mutations in UBA1, which are disease-defining for VEXAS syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet PCR profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established 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=2,027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n=12) and unknown significance (n=15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO2016 as MDS-MLD/SLD. Patients had a median of one additional myeloid gene mutation, often in TET2 (n=12), DNMT3A (n=10), ASXL1 (n=3), or SF3B1 (n=3). Retrospective clinical review where possible showed that 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS.