sJIA Linked With Rare Gene Variants in Large-Scale Targeted Sequencing Study

Results from a large-scale targeted sequencing study showed a potential link between hereditary periodic fever syndrome (HPF) and familial hemophagocytic lymphohistiocytosis (fHLH) genes to the pathophysiology of systemic juvenile idiopathic arthritis (sJIA)1, according to researchers presenting at American College of Rheumatology Convergence 2022.

Systemic juvenile idiopathic arthritis is a genetically complex and systemic inflammatory condition with similar characteristics to HPF. Although previous studies investigated whether variants in HPF and familial HLH genes contributes to the pathophysiology of sJIA, sufficient statistical power could not be reached to make generalizable conclusions.

Enter Correia Marques and colleagues, who performed targeted sequencing of HPF (MEFV, MVK, NLRP12, NLRP3, NOD2, PSTPIP1, TNFRSF1A) and fHLH (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) in patients with sJIA (n = 480) and a control group (n = 365) from the International Childhood Arthritis Genetics Consortium cohort using Illumina Nextera Custom Capture Assays and Illumina sequencers. Researchers distributed rare variants among those with sJIA and compared the results to the distribution among INCHARGE healthy controls or simulated data from the 33,370 Non-Finnish European (NFE) reference subjects in the Exome Aggregation Consortium (ExAC) using rare variant association testing.

The sequencing of the 480 patients with sJIA identified 78 rare fHLH gene variants and 62 rare HPF gene variants. A comparison between the distribution of rare variants in patients with sJIA with that of the ExAC NFE population revealed associations between sJIA and LYST, STXBP2, UNC13D, and MEFV. The researchers also found rare, recurrent mutations of STXBP2, UNC13D, and MEFV among the sJIA cohort, including several that were not observed in the ExAC population.

“These results highlight the potential value of studying rare genetic variation in sJIA,” the authors concluded. “To expand this approach, we have established a collaborative infrastructure to perform an exome sequencing-based study of rare variation across all protein-coding genes in sJIA.”


—Anthony Calabro



  1. Correia Marques M, Rubin D, Shuldiner E, et al. Large-Scale Targeted Sequencing Study Links Systemic Juvenile Idiopathic Arthritis with Rare Variants of MEFV, LYST, STXBP2, UNC13D. Paper presented at: American College of Rheumatology Convergence 2022; November 10-14, 2022; Philadelphia, PA. Accessed November 11, 2022.