Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis

Abstract

ObjectivesTo determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 (UBA1).MethodsFourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1–78.0)). Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively.ResultsUBA1 was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic UBA1 variants (c.121A>C, c.121A>G or c.122T>C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A>C) in one female patient, which was subsequently confirmed by PNA-clamping PCR.ConclusionsGenetic screening for pathogenic UBA1 variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in UBA1 in the female patient is the first to be reported.

Thrombosis in VEXAS syndrome

“…VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome [1] is described as a late-onset autoinflammatory syndrome exhibiting a spectrum of systemic inflammatory manifestations as well as significant haematologic abnormalities such as macrocytic anaemia, marrow dysplasia, vacuolisation in myeloid cells [2] and thrombosis. Several published case series [1,[3][4][5][6][7][8][9][10] have observed a high prevalence of venous thromboembolism (VTE) in patients with VEXAS syndrome of between 10% and 56%, with a significant mortality rate (27%-50%). We report a case of VEXAS syndrome complicated by unprovoked venous thromboembolism, followed by a rapid review of available literature.…”

Risk factors for the recurrence of relapsing polychondritis

“…The condition was named VEXAS syndrome (15). Interestingly, Japanese patients with UBA1 gene mutations also have a high prevalence of myelodysplastic syndromes (16). Further studies are required to investigate the prevalence of the mutation of UBA1 gene in the general population among different ethnic groups.…”

Characteristic vacuolization of myeloid precursors and UBA1 mutation in a woman with monosomy X

“…UBA1 mutation has been recently described in a female patient, but in this case, variant allele frequency was very low (0,14%) and no cytogenetic analysis was performed. 3 Our case shows that, as the UBA1 gene is located on the X chromosome, VEXAS syndrome may also be observed in women with monosomy X. Therefore, in an unexplained inflammatory syndrome, screening of UBA1 mutation is required not only in men but also in women with typical vacuoles in myeloid precursors and monosomy X (Figure 1).…”