Redefining the Landscape: Acquired Mutations Driving Systemic Autoinflammatory Diseases

Area of Science:

• Genetics and Immunology
• Molecular Biology
• Clinical Medicine

Background:

• Mosaicism is an established cause of systemic autoinflammatory diseases (SAIDs).
• Previously identified in dominantly inherited SAIDs like CAPS and TRAPS, somatic variants now extend to late-onset conditions such as VEXAS syndrome.
• Understanding the role of acquired variants in SAIDs is crucial for diagnosis and management.

Purpose of the Study:

• To characterize the prevalence, spectrum, and clinical significance of acquired variants in patients with SAIDs.
• To investigate the frequency of low-level mosaicism in a large cohort of SAIDs patients.
• To identify specific mosaic variants and their association with disease phenotypes and complications.

Main Methods:

• Deep next-generation sequencing of an autoinflammatory gene panel was performed on 5530 patients referred to a national SAIDs reference center.
• Testing was designed to detect low-level mosaicism.
• Results were reviewed by a multidisciplinary team and correlated with clinical data from electronic medical records.

Main Results:

• SAIDs were diagnosed in 7.3% of patients; mosaic variants were found in 20.6% of these diagnosed individuals.
• VEXAS syndrome (69%) and Cryopyrin-Associated Periodic Syndromes (CAPS) (24%) were the most common SAIDs associated with mosaic variants.
• Twenty-three distinct mosaic variants were identified, with eight having a minor allele frequency of ≤5%. AA amyloidosis complicated late-onset mosaic CAPS in 20% of patients.

Conclusions:

• Somatic mosaicism is a frequent underlying mechanism for late-onset SAIDs.
• These late-onset SAIDs are often diagnosed late and present a significant risk for developing AA amyloidosis.
• This study reports the largest genetically heterogeneous single-center cohort of mosaic SAIDs to date.