Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies

Abstract

UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEXAS syndrome, a predominantly male disease. Here we present a patient with clinical features of VEXAS who harbored two novel somatic variants in UBA1 (I894S and N606I). To better understand the clinical relevance and biological consequences of non-M41 (UBA1non-M41) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1non-M41 putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1non-M41 putative somatic variants either had vacuoles or immunodysregulatory symptoms. Analysis of the transcriptome confirmed neutrophil activation in VEXAS patients compared to healthy controls but did not result in a specific transcriptomic signature of UBA1M41 patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1non-M41 variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome.

Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases

“…However, the relative contributions of loss of UBA1b versus gain of UBA1c in terms of disease pathogenesis have remained unclear. In addition, recent reports, including ours, suggest that mutations at other sites than p.Met41 can cause VEXAS syndrome, highlighting the existence of disease mechanisms distinct from the canonical loss of cytoplasmic UBA1 activity, but molecular details have remained elusive (Faurel et al, 2023;Poulter et al, 2021;Sakuma et al, 2023;Stiburkova et al, 2023).…”

VEXAS‐Syndrom, eine neu beschriebene autoinflammatorische Systemerkrankung mit dermatologischen Manifestationen

“…Jüngst wurden weitere pathogene, somatische Mutationen im UBA1 ‐Gen beschrieben, unter anderem c.167C>T im Kodon 56, c.1861A > T im Kodon 621 sowie Splice‐Varianten (c.118‐1G > C und c.118‐2A > G), 4,8,9,10 deren funktionelle Auswirkungen noch nicht vollumfänglich verstanden sind. Individuen mit UBA1 ‐Mutation zeigen zudem mitunter weitere Mutationen, beispielsweise in den DNMT3A ‐ und TET2 ‐Genen 11,12 …”

VEXAS‐Syndrome, a newly described autoinflammatory systemic disease with dermatologic manifestations

“…1,6,7 Additional pathogenetic, somatic mutations in the UBA1 gene have recently been reported, including c.167C > T in codon 56, c.1861A > T in codon 621, as well as splice variants (c.118-1G > C, and c.118-2A > G). 4,8,9,10 The functional consequences of these mutations are not fully understood at this point in time. Individuals with UBA1 mutation also sometimes display additional mutations, for instance in the DNMT3A and TET2 genes.…”