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 (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, 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.

Cancer Center Humanitas Research Hospital and Humanitas University Milan Italy

Clinics of Hematology and Medical Oncology INDIGHO Laboratories University Medical Center Göttingen Germany

Clinics of Hematology and Medical Oncology University Medical Center Göttingen Georg August University Göttingen Germany

Computational Oncology Service Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY

Department of Biomedical and Neuromotor Sciences Cell Signalling Laboratory University of Bologna Bologna Italy

Department of Biomedicine and Prevention University of Rome Tor Vergata Rome Italy

Department of Clinical Medicine Federal University of Ceará Fortaleza Brazil

Department of Genomics Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Hematology Amsterdam University Medical Center Vrije University Medical Center Amsterdam The Netherlands

Department of Hematology and Genetics Unit University Hospital La Fe Valencia Spain

Department of Hematology Democritus Thrace University School of Medicine Alexandroupolis Greece

Department of Hematology Hemostasis Oncology and Stem Cell Transplantation Hannover Medical School Hannover Germany

Department of Hematology Hôpital Saint Louis Assistance Publique Hôpitaux de Paris Université de Paris Paris France

Department of Hematology Hospital Universitario y Politécnico La Fe Health Research Institute La Fe Valencia Spain

Department of Hematology Oncology and Clinical Immunology Heinrich Heine Universität Düsseldorf Germany

Department of Hematology Oncology and Clinical Immunology Universitatsklinik Dusseldorf Dusseldorf Germany

Department of Hematology Université de Paris Saint Louis Hospital Paris France

Department of Internal Medicine 1 Division of Hematology and Hemostaseology Medical University of Vienna Vienna Austria

Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden

Department of Laboratory Medicine Laboratory of Hematology Radboud University Medical Center Nijmegen The Netherlands

Department of Laboratory Medicine Medical University of Vienna Austria

Department of Medical Oncology Dana Farber Cancer Institute Boston MA

Department of Medicine 1 Hematology Cellular Therapy Hemostaseology and Infectious Diseases University Medical Center Leipzig Leipzig Germany

Department of Medicine Center for Hematology and Regenerative Medicine Karolinska Institutet Stockholm Sweden

Department of Medicine Huddinge Center for Hematology and Regenerative Medicine Karolinska University Hospital Stockholm Sweden

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt University Medical Center Nashville TN

Department of Molecular Medicine University of Pavia Pavia Italy

Department of Pathology and Cancer Diagnostics Karolinska University Hospital Stockholm Sweden

Department of Pathology and Tumor Biology Kyoto University Graduate School of Medicine Kyoto Japan

Department of Pathology Harvard Medical School Boston MA

Department of Pathology New York University Grossman School of Medicine New York NY

Department of Translational Hematology and Oncology Research Taussig Cancer Institute Cleveland Clinic Cleveland OH

Division of Hematology Oncology Chang Gung Memorial Hospital and Chang Gung University Taoyuan Taiwan

Division of Rheumatology Department of Medicine NYU Grossman School of Medicine New York NY

Experimental Hematology Unit Vall d'Hebron Institute of Oncology Barcelona Spain

Fondazione Istituto di Ricovero e Cura Carattere Scientifico Policlinico San Matteo University of Pavia Pavia Italy

Hematology Department Institut Català d'Oncologia Hospital Universitari Germans Trias i Pujol Josep Carreras Leukaemia Research Institute Universitat Autònoma de Barcelona Badalona Spain

Hematology Division Department of Medicine Stanford Cancer Center Stanford University Stanford CA

Hematology Laboratory Assistance Publique Hôpitaux de Paris Centre Université de Paris Cité Cochin Hospital Paris France

Howard Hughes Medical Institute Boston MA

Institut Cochin Université de Paris Cité Paris France

Institute of Hematology Sèragnoli IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Integrated Genomics Operation Memorial Sloan Kettering Cancer Center New York NY

Leukemia Service Memorial Sloan Kettering Cancer Center New York NY

Louis 5 Gerstner Jr Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center New York NY

Ludwig Boltzmann Institute for Hematology and Oncology Medical University of Vienna Vienna Austria

Medical Clinic and Policlinic 1 Hematology and Cellular Therapy University Leipzig Medical Center Leipzig Germany

Moores Cancer Center at University of California San Diego La Jolla CA

Myelodysplastic Syndromes Research Group Josep Carreras Leukaemia Research Institute Badalona Barcelona Spain

Myelodysplastic Syndromes Unit Department of Experimental and Clinical Medicine Hematology Azienda Ospedaliero Universitaria Careggi University of Florence Florence Italy

Nuffield Division of Clinical Laboratory Sciences Bloodwise Molecular Haematology Unit University of Oxford John Radcliffe Hospital Oxford United Kingdom

Oncology Hematology Center Hospital Israelita Albert Einstein São Paulo Brazil

Phase 1 Unit Center for Clinical Cancer Studies Karolinska University Hospital Stockholm Sweden

Radcliffe Department of Medicine Oxford BRC Haematology Theme University of Oxford Oxford United Kingdom

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Blood. 2024 Sep 12;144(11):1140-1141. doi: 10.1182/blood.2024024971. PubMed

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