TO THE EDITOR:

Systemic autoinflammatory disorders encompass a heterogeneous group of monogenic disorders that are characterized by recurrent episodes of systemic and organ-specific inflammation.

Using a genotype-first approach, Beck et al recently described VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a new late-onset treatment-refractory inflammatory syndrome with associated hematological abnormalities. VEXAS is caused by acquired somatic mutations at methionine 41 (p.Met41) of UBA1, the major E1 enzyme responsible for initiating ubiquitylation. The mutations were predominantly found in myeloid lineages and were absent in lymphoid lineages. Functional analysis identified loss of the cytoplasmic isoform UBA1b, initiated from p.Met41, and the subsequent gain of a new isoform, UBA1c, as the underlying disease mechanisms. No additional variants, other than those at p.Met41, were identified, suggesting that mutation of this residue alone causes VEXAS.

Here, we report 10 additional cases of VEXAS and describe 2 new mutations as a cause...

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