Low-ratio somatic NLRC4 mutation causes late-onset autoinflammatory disease

Ann Rheum Dis. 2022 Aug;81(8):1173-1178. doi: 10.1136/annrheumdis-2021-221708. Epub 2022 Apr 15.


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.

Keywords: arthritis; arthritis, rheumatoid; immune system diseases; inflammation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CARD Signaling Adaptor Proteins* / genetics
  • Calcium-Binding Proteins / genetics
  • Cytokines / metabolism
  • Hereditary Autoinflammatory Diseases* / genetics
  • Humans
  • Inflammasomes / metabolism
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics


  • CARD Signaling Adaptor Proteins
  • Calcium-Binding Proteins
  • Cytokines
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRC4 protein, human