Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies.
Maki SakumaPiers BlomberyManja MeggendorferClaudia HaferlachMarkus LindauerUwe M MartensWolfgang KernTorsten HaferlachWencke WalterPublished in: Leukemia (2023)
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 (UBA1 non-M41 ) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1 non-M41 putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1 non-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 UBA1 M41 patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1 non-M41 variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome.
Keyphrases
- copy number
- end stage renal disease
- newly diagnosed
- ejection fraction
- chronic kidney disease
- bone marrow
- prognostic factors
- single cell
- genome wide
- acute myeloid leukemia
- immune response
- rna seq
- patient reported outcomes
- depressive symptoms
- signaling pathway
- induced apoptosis
- dna methylation
- transcription factor
- early onset
- artificial intelligence
- electronic health record
- drug induced
- african american
- sleep quality
- pi k akt
- reactive oxygen species