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Low-ratio somatic NLRC4 mutation causes late-onset autoinflammatory disease
  1. Jun Wang1,2,
  2. Qiao Ye3,
  3. Wenjie Zheng4,
  4. Xiaomin Yu2,
  5. Fang Luo3,
  6. Ran Fang1,2,
  7. Yaoyao Shangguan4,
  8. Zhijun Du5,
  9. Pui Y Lee6,
  10. Taijie Jin1,2,
  11. Qing Zhou1,2
  1. 1 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
  2. 2 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
  3. 3 The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
  4. 4 The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
  5. 5 MyGenostics Inc, Beijing, China
  6. 6 Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Qing Zhou, Zhejiang University, Hangzhou, Zhejiang, China; zhouq2{at}; Dr Taijie Jin, Zhejiang University, Hangzhou, Zhejiang, China; jintaijie{at}


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.

  • inflammation
  • immune system diseases
  • arthritis
  • arthritis, rheumatoid

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  • Handling editor Josef S Smolen

  • JW, QY and WZ contributed equally.

  • Contributors QZ, TJ designed the study, directed and supervised the research. TJ, JW, XY and RF performed experiments and analysed the data. QY, WZ, FL, YS, ZD and PYL enrolled the patients, collected and interpreted clinical information. QZ, TJ, JW and PYL wrote the manuscript with input from others. All authors contributed to the review and approval of the manuscript. QZ is the author acting as guarantor.

  • Funding QZ received the grant 2018YFC1004903 from National Key Research and Development Project, grants 31771548 and 81971528 from the National Natural Science Foundation of China, grant LR19H100001 from Zhejiang Provincial Natural Science Foundation of China.

  • Competing interests ZD is the employee of MyGenostics.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.