Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis

Ferrada, Marcela; Savic, Sinisa; Cardona, Daniela Ospina; Collins, Jason C.; Alessi, Hugh; Gutierrez-Rodrigues, Fernanda; Kumar, Dinesh Babu Uthaya; Wilson, Lorena; Goodspeed, Wendy; Topilow, James S; Paik, Julie J; Poulter, James A.; Kermani, Tanaz A.; Koster, Matthew J.; Warrington, Kenneth J.; Cargo, Catherine; Tattersall, Rachel; Duncan, Christopher J A; Cantor, Anna; Hoffmann, Patrycja; Payne, Elspeth; Bonnekoh, Hanna; Krause, Karoline; Cowen, Edward W.; Calvo, Katherine R.; Patel, Bhavisha; Ombrello, Amanda K.; Kastner, Daniel L.; Young, Neal S.; Werner, Achim; Grayson, Peter C.; Beck, David B.

doi:10.1182/blood.2022016985

Cited by 89 publications

(121 citation statements)

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“…To date, all pathogenic mutations associated with VEXAS have been confined to exon 3, with methionine-41 (Met41) being a particularly important site. 1,2 No patients demonstrated any of the known pathogenic mutations in UBA1, but four patients were found to have rare variants outside exon 3 that have not been previously reported and have unknown functional consequences. The variants identified (and variant allele frequencies) were: c.2554-1G>T (0.5), c.2554-8C>T (0.4), c.2374C>T:p.Gln792Ter (0.14) and c.1321G>A:p.Glu441Ter (0.8).…”

Section: Allogeneic Haematopoietic Stem Cell Transplantation For Vexa...mentioning

confidence: 86%

Allogeneic haematopoietic stem cell transplantation for VEXAS syndrome: UK experience

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Section: Allogeneic Haematopoietic Stem Cell Transplantation For Vexa...mentioning

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Allogeneic haematopoietic stem cell transplantation for VEXAS syndrome: UK experience

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“…We also demonstrate for the first time that the variant can precede onset of clinical symptoms. Further highlighting the strength of an unbiased genomic ascertainment approach to identify patients with VEXAS from within the general population, we observed a different proportion of VEXAS-defining mutations compared to two recent phenotypically defined cohort studies in VEXAS 8,9 , and we identified an additional likely disease-causing variant. Finally, we also observed a greater proportion of euploid females with pathogenic variants in UBA1 than previously reported.…”

Section: Main Textmentioning

confidence: 57%

“…Patients with VEXAS syndrome have rheumatologic, hematologic, dermatologic and pulmonary manifestations thought to be caused by inflammation and can carry a variety of clinical diagnoses including polyarteritis nodosa (PAN), relapsing polychondritis (RP), giant cell arteritis (GCA), Sweet syndrome (SS) and myelodysplastic syndrome (MDS). Prognosis in VEXAS is determined more by the molecular than clinical diagnosis 8 . Previous work on UBA1/ VEXAS was largely phenotype-driven with ascertainment based on similarity to the original reported manifestations of VEXAS syndrome 8,9 .…”

Section: Main Textmentioning

confidence: 99%

“…Prognosis in VEXAS is determined more by the molecular than clinical diagnosis 8 . Previous work on UBA1/ VEXAS was largely phenotype-driven with ascertainment based on similarity to the original reported manifestations of VEXAS syndrome 8,9 .…”

Section: Main Textmentioning

confidence: 99%

“…Finally, we also observed a greater proportion of euploid females with pathogenic variants in UBA1 than previously reported. 15 Despite the large number of cases reported to date, UBA1 is still not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels 8,9 . Defining the clinical spectrum of UBA1, using biobanks, is a necessary step to better define disease criteria and testing recommendations.…”

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confidence: 99%

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Genomic ascertainment for UBA1 variants and VEXAS syndrome: a population-based study

Beck

Bodian²,

Shah

et al. 2022

Preprint

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Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. This study used a genomic ascertainment approach to overcome these limitations and better define UBA1-related disease. Objective: Determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting and Participants: This cohort study evaluated UBA1 variants in exome data from 163,096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record (EHR) data up to January 1st, 2022. Main outcomes and measures: Prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other symptoms in individuals with somatic UBA1 variation; structured and manual review of EHR; review of bone marrow biopsies; survival in carriers of somatic UBA1 variation. Results: In a retrospective study of 163,096 participants (mean age 52.8 years; 94% of European ancestry, 61% female), 11 individuals harbored somatic, known pathogenic UBA1 variants, with 100% having clinical manifestations consistent with VEXAS syndrome. We found a previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) in a symptomatic patient. Disease-causing UBA1 variants were found in ~1 in 14,000 unrelated individuals, and ~1 in 4,000 men >50 years old. A disease-causing UBA1 variant confers a ~ 6.6 higher probability of mortality vs. age-, sex-, and BMI-matched non-carriers. The majority (7, 58%) of individuals did not meet criteria for rheumatologic and hematologic diagnoses previously associated with VEXAS syndrome, however all individuals had anemia (mean 7.8 g/dL, median 7.5g/dL), mostly macrocytic (91%) with concomitant thrombocytopenia (91%). Finally, we identified a pathogenic variant in one male prior to onset of VEXAS-related signs or symptoms and two females had disease with heterozygous variants. Conclusions and relevance: This cohort study showed that the prevalence, penetrance, and expressivity of pathogenic UBA1 variants were higher than expected. More expansive UBA1 testing will lead to molecular diagnoses and improved treatment for patients.

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Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Beck

Bodian

Shah

et al. 2023

JAMA

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ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes.ObjectiveTo determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.Design, Setting, and ParticipantsThis retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022.ExposuresExome sequencing was performed.Main Outcomes and MeasuresOutcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.ResultsIn 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A&gt;T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).Conclusions and RelevanceThis study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

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Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis

Cited by 89 publications

References 29 publications

Allogeneic haematopoietic stem cell transplantation for VEXAS syndrome: UK experience

Allogeneic haematopoietic stem cell transplantation for VEXAS syndrome: UK experience

Genomic ascertainment for UBA1 variants and VEXAS syndrome: a population-based study

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

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