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Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome. | LitMetric

AI Article Synopsis

  • VEXAS syndrome is an immune disorder linked to specific mutations in the UBA1 gene, particularly affecting older individuals with recurrent inflammation.
  • This study identifies a novel splice site variant (c.346-2A>G) in two unrelated adult male patients, leading to abnormal mRNA splicing and diverse inflammatory symptoms.
  • The findings highlight the importance of comprehensive genetic testing for UBA1 variants in patients suspected of having VEXAS syndrome to better understand the range of genetic causes associated with this condition.

Article Abstract

Objective: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p.Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome.

Methods: Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were undertaken by both Sanger and amplicon-based deep sequencing, and mRNA studies were undertaken by both cDNA subcloning and mRNA sequencing.

Results: We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis of the patients' samples indicated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5.

Conclusion: Here we describe abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant, identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and provide support for a complete gene evaluation in those patients considered candidates for VEXAS syndrome.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443021PMC
http://dx.doi.org/10.1093/rheumatology/keae201DOI Listing

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