• David B Beck, Marcela A Ferrada, Keith A Sikora, Amanda K Ombrello, Jason C Collins, Wuhong Pei, Nicholas Balanda, Daron L Ross, Daniela Ospina Cardona, Zhijie Wu, Bhavisha Patel, Kalpana Manthiram, Emma M Groarke, Fernanda Gutierrez-Rodrigues, Patrycja Hoffmann, Sofia Rosenzweig, Shuichiro Nakabo, Laura W Dillon, Christopher S Hourigan, Wanxia L Tsai, Sarthak Gupta, Carmelo Carmona-Rivera, Anthony J Asmar, Lisha Xu, Hirotsugu Oda, Wendy Goodspeed, Karyl S Barron, Michele Nehrebecky, Anne Jones, Ryan S Laird, Natalie Deuitch, Dorota Rowczenio, Emily Rominger, Kristina V Wells, LeeChyi-Chia RCRFrom the National Human Genome Research Institute (D.B.B., A.K.O., W.P., N.B., D.L.R., D.O.C., K.M., P.H., S.R., L.X., H.O., M.N., A.J., R.S.L., N.D., J.J.C., M.C.V.M., D.N., B.D.S., W.A.G., S.M.B., I.A., D.L.K.), the National Institute of, Weixin Wang, Megan Trick, James Mullikin, Gustaf Wigerblad, Stephen Brooks, Stefania Dell'Orso, Zuoming Deng, Jae J Chae, Alina Dulau-Florea, May C V Malicdan, Danica Novacic, Robert A Colbert, Mariana J Kaplan, Massimo Gadina, Sinisa Savic, Helen J Lachmann, Mones Abu-Asab, Benjamin D Solomon, Kyle Retterer, William A Gahl, Shawn M Burgess, Ivona Aksentijevich, Neal S Young, Katherine R Calvo, Achim Werner, Daniel L Kastner, and Peter C Grayson.
• From the National Human Genome Research Institute (D.B.B., A.K.O., W.P., N.B., D.L.R., D.O.C., K.M., P.H., S.R., L.X., H.O., M.N., A.J., R.S.L., N.D., J.J.C., M.C.V.M., D.N., B.D.S., W.A.G., S.M.B., I.A., D.L.K.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (M.A.F., K.A.S., S.N., W.L.T., S.G., C.C.-R., W.G., E.R., K.V.W., G.W., S.B., S.D., Z.D., R.A.C., M.J.K., M.G., P.C.G.), the National Institute of Dental and Craniofacial Research (J.C.C., A.J.A., A.W.), the Undiagnosed Diseases Program, Common Fund, Office of the Director (N.B., D.L.R., M.C.V.M., D.N., W.A.G.), the Hematology Branch, National Heart, Lung, and Blood Institute (Z.W., B.P., E.M.G., F.G.-R., L.W.D., C.S.H., N.S.Y.), the National Institute of Allergy and Infectious Diseases (K.S.B.), the Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (C.-C.R.L.), the National Institutes of Health (NIH) Intramural Sequencing Center, National Human Genome Research Institute (J.M.), the Department of Laboratory Medicine (W.W., M.T., A.D.-F., K.R.C.), and the National Eye Institute (M.A.-A.), NIH, Bethesda, and GeneDx, Gaithersburg (K.R.) - both in Maryland; and the National Amyloidosis Centre, Royal Free Hospital London NHS Foundation Trust and University College London, London (D.R., H.J.L.), and the National Institute for Health Research-Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds (S.S.) - both in the United Kingdom.
• N. Engl. J. Med. 2020 Dec 31; 383 (27): 262826382628-2638.

BackgroundAdult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.MethodsWe analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.ResultsWe identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.ConclusionsUsing a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).Copyright © 2020 Massachusetts Medical Society.

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