Redefining the Landscape: Acquired Mutations Driving Systemic Autoinflammatory Diseases

Mosaicism is a recognized cause of systemic autoinflammatory diseases (SAIDs). Initially described in cryopyrin-associated periodic syndromes (CAPS), it has since been reported in several dominantly inherited SAIDs, including Blau syndrome, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), stimulator of interferon genes-associated vasculopathy with onset in infancy, NLRC4 inflammasomopathies, and familial Mediterranean fever. Recently, somatic variants underlying vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) have extended this to late-onset disease. This study aimed to characterize the prevalence, spectrum, and clinical significance of acquired variants in SAIDs.

A total of 5,530 patients referred to a national SAIDs reference center between 2017 and 2025 underwent deep next-generation sequencing autoinflammatory gene panel testing to detect low-level mosaicism. Results underwent multidisciplinary review and correlation with clinical data from electronic medical records.

SAID diagnoses were made in 403 of 5,530 patients (7.3%, 95% confidence interval [CI] 6.6%-8.0%). Among these, mosaic variants were identified in 83 patients (20.6%, 95% CI 16.9%-24.8%), including patients with VEXAS syndrome (69%), CAPS (24%), TRAPS (5%), Blau syndrome (1%), and NLRC4 inflammasomopathies (1%). Twenty-three distinct mosaic variants were identified across different SAIDs genes; in eight, the minor allele frequency was ≤5%. We report the first case of vertical transmission of TRAPS due to gonosomal mosaicism. AA amyloidosis complicated the disease course in 20% of patients diagnosed with late-onset mosaic CAPS.

Somatic mosaicism is a frequent mechanism underlying late-onset SAIDs, which are often diagnosed late and carry a high risk of AA amyloidosis. To our knowledge, this represents the largest genetically heterogeneous single-center cohort of individuals with mosaic SAIDs reported to date.