作者
Maria Sirenko,Elsa Bernard,Maria Creignou,Dylan Domenico,Andrea Farina,Juan Arango Ossa,Olivier Kosmider,Robert P. Hasserjian,Martin Jädersten,Ulrich Germing,Guillermo Sanz,Arjan A. van de Loosdrecht,Carmelo Gurnari,Matilde Y. Follo,Felicitas Thol,Lurdes Zamora,Andrea Pellagatti,Harold K. Elias,Detlef 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 Huberman,Pierre Fenaux,Monika Beličková,Michael R. Savona,Virginia M. Klimek,Fábio Pires de Souza Santos,Jacqueline Boultwood,Ιoannis Kotsianidis,Valeria Santini,Françesc Solé,Uwe Platzbecker,Michael Heuser,Peter Valent,Carlo Finelli,Maria Teresa Voso,Lee‐Yung Shih,Seishi Ogawa,Michaëla Fontenay,Joop H. Jansen,José Cervera,Benjamin L. Ebert,Rafael Bejar,Peter L. Greenberg,Norbert Vey,Luca Malcovati,Mario Cazzola,David B. Beck,Eva S Hellstrom-Lindberg,Elli Papaemmanuil,Ronald Feitosa Pinheiro
摘要
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.