Redefining the Landscape: Acquired Mutations Driving Systemic Autoinflammatory Diseases.

Abstract

Mosaicism is a recognised 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, TNF Receptor-Associated Periodic Syndrome (TRAPS), STING-Associated Vasculopathy with Onset in Infancy (SAVI), NLRC4 inflammasomopathies, and familial Mediterranean fever (FMF). Recently, somatic variants underlying Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (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. 5530 patients referred to a national SAIDs reference centre between 2017-2025 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. SAIDs diagnosis was made in 403/5530 patients (7.3%, 95% CI 6.6-8.0%). Among these, mosaic variants were identified in 83 patients (20.6%, 95% CI 16.9-24.8%), including VEXAS (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-centre cohort of mosaic SAIDs reported to date.