Background: Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are severe, life-threatening systemic hyperinflammatory syndromes. They can arise from genetic defects as well as various triggers, including infections, malignancies, and autoimmune diseases. MAS is most recognised and best studied in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Currently, research on the underlying pathogenesis of MAS and its treatment options remains insufficient. Recently, the field of genomics has garnered increasing attention.

Objectives: The objective of this study is to identify the genetic variants associated with AOSD-MAS susceptibility and to elucidate their connections to specific target genes. Such insights are critical for advancing the clinical translation of genetic discoveries, thereby enhancing the accuracy of diagnostic genetic screenings and informing personalized therapeutic strategies.

Methods: In this study, we performed whole-exome sequencing (WES) on a cohort of AOSD patients to identify potential genetic variations, followed by Sanger sequencing for validation. RNA sequencing (RNA-seq) was conducted to explore gene expression profiles. Statistical analyses were carried out using Fisher’s exact test (two-sided) to assess associations, and survival analysis was employed to evaluate outcomes.

Results: This study investigated the genetic predisposition of AOSD-MAS, highlighting the critical involvement of known causative genes for primary HLH (pHLH-KG) and the candidate genes in AOSD-MAS. Among the 72 AOSD-MAS patients, 19 individuals (19/72, 26.39%) harbored mutations in pHLH-KG genes, including LYST, PRF1, STX11, UNC13D, NLRC4, STXBP2, AP3B1, CTPS1, RASGRP1, NCKAP1L, and RC3H1 . Gene level comparisons demonstrated that ADGRE2, TGFB1, C6, IKZF3, MPO, POLD1, LIFR, IL15RA , and FANCC were significantly enriched in AOSD-MAS compared to AOSD without MAS (AOSD-nMAS), with notable differences (log2OR > 1 or infinite, p-value < 0.05). At the variant level, significant differences were observed for LYST p.I2666N, STX11 p.A125V, POLA1 p.V539M, LRBA p.E88A, ERCC4 p.G912R, and ADGRE2 p.C29Y (p-value < 0.05). These findings strongly suggest that ADGRE2 plays a pivotal role in the pathogenesis of AOSD-MAS. Additionally, we also conducted gene-phenotype correlation analysis, which revealed that CSF2RB and MECOM were significantly more prominent in refractory AOSD-MAS. In conclusion, the potential synergistic interactions among these genes may contribute critically to the development of AOSD-MAS.

Conclusion: Our study identified mutations in known HLH-associated genes as well as new candidate genes in AOSD-MAS through WES. Gene-phenotype correlation analysis revealed differences in gene profiles across different clinical phenotypes, providing insights for the precision therapies for AOSD-MAS.

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.