Background: Adult-onset Still’s disease (AOSD), a rare but clinical well-known autoinflammatory disease, is characterized by a high spiking fever, evanescent eruption, sore throat, and arthralgia, with multi-systems and multi-organ involvement. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity.

Objectives: The objective of this research is to identify novel AOSD susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit.

Methods: To identify deleterious mutations, we analyzed peripheral-blood exome sequence data in a cohort of 344 patients with AOSD independent of clinical phenotype and inheritance pattern. Sanger sequencing was performed to validate the mutations. Transcriptome profiles were obtained from bulk RNA sequencing of peripheral blood mononuclear cells (PBMCs) and neutrophils. In vitro transfection models, immunoblotting, and qPCR were used to assess gene function.

Results: In this study, whole-exome sequencing of 334 AOSD patients revealed mutations in 33 genes from a panel of 56 known autoinflammatory disease (AID) causative genes. A total of 83 variants were identified across these genes, involving 76 cases (76/334, 22.75%), with NOD2 mutations being the most prevalent. In addition, 64 variants were identified in 21 candidate AID genes, affecting 60 cases (60/334, 17.96%). The top three variants ( OAS1 : p.V135I, NFKB1 : p.T39A, SIGLEC1 : p.R1006C) were associated with the type I interferon and NF-kB pathways. Transcriptome profile analysis of patient-derived PBMCs and neutrophils identified significant gene expression changes in the activation of innate immune cells and inflammatory response pathways, and contributed to the candidate gene panel for AOSD. Association analysis of the AOSD cohort and 5,000 individuals without AOSD identified multiple novel missense mutations significantly enriched in the AOSD group, including TMEM64 , VSTM4 , COL12A1 , TSC2 , GRIN3B , and others. In vitro experiments demonstrated that TSC2 mutation ( TSC2 : p.R537C) activates the mTOR pathway. Further genotype-phenotype correlation analyses revealed that patients classified as polycyclic or chronic subtypes harbored a higher mutation burden compared to those with the monocyclic subtype, suggesting a potential synergistic pathogenic effect among these genes.

Conclusion: This study examined mutations in known AID and candidate genes in AOSD, identifying novel genes through case-control association analysis and in vitro experiments. Furthermore, a genotype-phenotype analysis was conducted. These findings provide valuable insights into the genetic landscape of AOSD.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.