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Sequence data from control participants were obtained in silico (database of Genotypes and Phenotypes: phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test package. Significance was defined as <jats:italic>P<\/jats:italic> &lt; 0.05 after 100,000 permutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sequencing data from 524 sJIA cases were jointly called and harmonized with exome\u2010derived target data from 3,000 controls. Quality control operations produced a set of 480 cases and 2,924 ancestrally matched control participants. RVT of cases and controls revealed a significant association with rare protein\u2010altering variants (minor allele frequency [MAF] &lt; 0.01) of <jats:italic>STXBP2<\/jats:italic> (<jats:italic>P<\/jats:italic> = 0.020) and ultrarare variants (MAF &lt; 0.001) of <jats:italic>STXBP2<\/jats:italic> (<jats:italic>P<\/jats:italic> = 0.006) and <jats:italic>UNC13D<\/jats:italic> (<jats:italic>P<\/jats:italic> = 0.046). A subanalysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare <jats:italic>UNC13D<\/jats:italic> variants (<jats:italic>P<\/jats:italic> = 0.0047) between the groups. Additionally, patients with sJIA more often carried two or more HLH variants than did controls (<jats:italic>P<\/jats:italic> = 0.007), driven largely by digenic combinations involving <jats:italic>LYST<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified an enrichment of rare HLH variants in patients with sJIA compared with controls, driven by <jats:italic>STXBP2<\/jats:italic> and <jats:italic>UNC13D.<\/jats:italic> Biallelic variation in HLH genes was associated with sJIA, driven by <jats:italic>LYST<\/jats:italic>. Only <jats:italic>UNC13D<\/jats:italic> displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42938-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42938","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T21:49:00Z","timestamp":1719524940000},"page":"1566-1572","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis"],"prefix":"10.1002","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1195-1595","authenticated-orcid":false,"given":"Mariana","family":"Correia Marques","sequence":"first","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Rubin","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily G.","family":"Shuldiner","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mallika","family":"Datta","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Schmitz","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Gutierrez Cruz","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Patt","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Bennett","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Grom","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center  Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1946-3916","authenticated-orcid":false,"given":"Dirk","family":"Foell","sequence":"additional","affiliation":[{"name":"University Hospital Muenster  Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0704-1916","authenticated-orcid":false,"given":"Marco","family":"Gattorno","sequence":"additional","affiliation":[{"name":"IRCCS Istituto G. 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