LAUSR

Objectives We aim to investigate the genetic basis of a case of late-onset autoinflammatory disease characterised by arthritis, recurrent fever and skin rashes. Methods We performed whole-exome/genome sequencing and digital droplet PCR (ddPCR) to identify the pathogenic somatic mutation. We used single-cell RNA sequencing (scRNA-seq), intracellular cytokine staining, quantitative PCR, immunohistochemistry and western blotting to define inflammatory signatures and to explore the pathogenic mechanism. Results We identified a somatic mutation in NLRC4 (p.His443Gln) with the highest mosaicism ratio in the patient’s monocytes (5.69%). The somatic mutation resulted in constitutive NLRC4 activation, spontaneous apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) aggregation, caspase-1 hyperactivation and increased production of interleukin (IL)-1β and IL-18. Moreover, we demonstrated effective suppression of inflammatory cytokine production by targeting gasdermin D, an approach that could be considered as a novel treatment strategy for patients with NLRC4-associated autoinflammatory syndrome. Conclusions We reported a case of a late-onset autoinflammatory disease caused by a somatic NLRC4 mutation in a small subset of leucocytes. We systemically analysed this condition at a single-cell transcriptomic level and revealed specific enhancement of inflammatory response in myeloid cells.