Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes
Maria Sirenko, Elsa Bernard, Maria Creignou, Dylan Domenico, Andrea Farina, Juan Esteban Arango Ossa, Olivier Kosmider, Robert P Hasserjian, Martin Jädersten, Ulrich Germing, Guillermo F. Sanz, Arjan A. van de Loosdrecht, Carmelo Gurnari, Matilde Y Follo, Felicitas R. Thol, Lurdes Zamora, Andrea Pellagatti, Harold Kunal Elias, Detlef Thomas Haase, Birgitta Sander, Elisa Orna, Katharina Zoldan, Lea Naomi Eder, Wolfgang R Sperr, Renate Thalhammer, Christina Ganster, Lionel Adès, Magnus Tobiasson, Laura Palomo, Matteo Giovanni Della Porta, Kety H Huberman, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia Klimek, Fabio P S Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Sole, Uwe Platzbecker, Michael Heuser, Peter Valent, Carlo Finelli, Maria Teresa Voso, Lee Yung Shih, Seishi Ogawa, Michaela Fontenay, Joop H Jansen, José Cervera, Benjamin L Ebert, Rafael Bejar, Peter L. Greenberg, Norbert Gattermann, Luca Malcovati, Mario Cazzola, David B. Beck, Eva S Hellstrom-Lindberg, Elli Papaemmanuil, Ronald Feitosa PinheiroMutations 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.