TOPLINE

Somatic mosaicism was noted in more than 1 in 5 patients with a systemic autoinflammatory disease (SAID) diagnosis, with a high prevalence among those with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Patients with late-onset mosaic cryopyrin-associated periodic syndromes (CAPS) experienced a diagnostic delay and appeared to have a risk for amyloidosis.

METHODOLOGY

• Researchers conducted a retrospective study at the UK's only nationally accredited reference center for SAIDs to identify and characterize patients referred for the evaluation of suspected SAIDs and assess the spectrum of acquired somatic mutations driving SAIDs.
• Between 2017 and 2025, 5530 patients with suspected monogenic autoinflammatory syndromes underwent deep next-generation sequencing using a targeted autoinflammatory gene panel validated to detect variant allele frequencies as low as 3%.
• Measures included mosaic variant identification, clinical phenotypes, and diagnostic challenges, and in patients with renal impairment caused by a long-term inflammatory condition, AA amyloidosis was evaluated.

TAKEAWAY

• Overall, 403 patients were diagnosed with SAIDs, of whom 21% harbored mosaic variants. Among patients with mosaic variants, patients with VEXAS syndrome were most common (69%), followed by those with CAPS (24%), TNF receptor-associated periodic syndrome (TRAPS; 5%), Blau syndrome (1%), or NLRC4 inflammasomopathies (1%); collectively, 23 distinct variants were identified across five disease-associated genes.
• Among patients who developed mosaic CAPS in adulthood (n = 15), diagnosis was delayed by a median of 10 years. Three of 15 patients developed AA amyloidosis.
• Among the 229 referrals received for suspected VEXAS syndrome from 2020 to August 2025, a diagnosis was confirmed in 57 patients, with a median age at onset of 68 years and a median diagnostic delay of 2.5 years.
• Of the patients diagnosed with gonosomal mosaicism, vertical transmission due to gonosomal mosaicism was noted in one patient — the mother carried a pathogenic TNFRSF1A variant in 9% of alleles, and her 4-year-old child had the likely pathogenic heterozygous variant and developed typical disease symptoms.

IN PRACTICE

"Detection of mosaic variants has important implications for diagnosis, prognosis, treatment selection, and genetic counseling. The rise of VEXAS syndrome reflects the evolving landscape of autoinflammatory disease diagnostics and emphasizes the critical importance of early incorporation of newly recognized genes, such as UBA1 testing, into diagnostic workflows," the authors of the study wrote.

SOURCE

The study was led by Dorota Rowczenio, PhD, Royal Free London NHS Foundation Trust in London, England. It was published online on July 30, 2026, in Arthritis & Rheumatology.

LIMITATIONS

The study used a targeted gene panel that only tested for known disease-associated genes, meaning variants in newly discovered genes or other genomic regions could have been missed. Thus, some patients may not have received a genetic diagnosis.

DISCLOSURES

No specific funding was reported for this study. One author reported receiving British Heart Foundation Clinical Research Training Fellowship June 2020-2023 paid to employing institution.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.