A large retrospective study out of the UK's only nationally accredited reference center for systemic autoinflammatory diseases (SAIDs) has found that somatic mosaicism — where acquired genetic mutations occur in only a subset of cells — is far more common than previously recognized, accounting for over 1 in 5 SAID diagnoses. Researchers analyzed deep next-generation sequencing data from 5,530 patients between 2017 and 2025, identifying 23 distinct mosaic variants across five disease-associated genes.

Among the 403 confirmed SAID patients, VEXAS syndrome was the most prevalent mosaic condition (69%), followed by cryopyrin-associated periodic syndromes (CAPS) at 24%. Patients with adult-onset mosaic CAPS faced a median diagnostic delay of 10 years, with some developing AA amyloidosis — a serious complication of chronic inflammation. VEXAS patients had a median age of onset of 68 years and a 2.5-year diagnostic delay.

Key Takeaways:

• Somatic mosaicism was found in 21% of confirmed SAID patients — a significant and often overlooked driver of disease
• VEXAS syndrome accounted for 69% of mosaic cases; early UBA1 gene testing should be incorporated into diagnostic panels
• A 10-year diagnostic delay in mosaic CAPS patients highlights the risk of missed or late diagnoses — and downstream complications like amyloidosis
• Gonosomal mosaicism can be transmitted vertically, with one case showing a mother passing a pathogenic variant to her child

Why it matters: These findings reframe how clinicians should approach autoinflammatory disease workups. Somatic mutations aren't rare edge cases — they're a major diagnostic category. Faster, broader genetic testing could prevent years of missed diagnoses and reduce the risk of life-altering complications.