{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:00:27Z","timestamp":1789419627622,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T00:00:00Z","timestamp":1416873600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1-AR059049"],"award-info":[{"award-number":["RO1-AR059049"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Macrophage activation syndrome (MAS), a life\u2010threatening complication of systemic juvenile idiopathic arthritis (JIA), resembles familial hemophagocytic lymphohistiocytosis (HLH), a constellation of autosomal\u2010recessive immune disorders resulting from deficiency in cytolytic pathway proteins. We undertook this study to test our hypothesis that MAS predisposition in systemic JIA could be attributed to rare gene sequence variants affecting the cytotolytic pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing was used in 14 patients with systemic JIA and MAS and in their parents to identify protein\u2010altering single\u2010nucleotide polymorphisms\/indels in known HLH\u2010associated genes. To discover new candidate genes, the entire whole\u2010exome sequencing data were filtered to identify protein\u2010altering, rare recessive homozygous, compound heterozygous, and de novo variants with the potential to affect the cytolytic pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Heterozygous protein\u2010altering rare variants in the known genes (<jats:italic>LYST,<\/jats:italic><jats:italic>MUNC13\u20104<\/jats:italic>, and <jats:italic>STXBP2<\/jats:italic>) were found in 5 of 14 patients with systemic JIA and MAS (35.7%). This was in contrast to only 4 variants in 4 of 29 patients with systemic JIA without MAS (13.8%). Homozygosity and compound heterozygosity analysis applied to the entire whole\u2010exome sequencing data in systemic JIA\/MAS revealed 3 recessive pairs in 3 genes and compound heterozygotes in 73 genes. We also identified 20 heterozygous rare protein\u2010altering variants that occurred in at least 2 patients. Many of the identified genes encoded proteins with a role in actin and microtubule reorganization and vesicle\u2010mediated transport. \u201cCellular assembly and organization\u201d was the top cellular function category based on Ingenuity Pathways Analysis (<jats:italic>P<\/jats:italic> &lt; 3.10 \u00d7 10<jats:sup>\u22125<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Whole\u2010exome sequencing performed in patients with systemic JIA and MAS identified rare protein\u2010altering variants in known HLH\u2010associated genes as well as in new candidate genes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38793","type":"journal-article","created":{"date-parts":[[2014,7,21]],"date-time":"2014-07-21T14:34:15Z","timestamp":1405953255000},"page":"3486-3495","source":"Crossref","is-referenced-by-count":193,"title":["Whole\u2010Exome Sequencing Reveals Overlap Between Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis and Familial Hemophagocytic Lymphohistiocytosis"],"prefix":"10.1002","volume":"66","author":[{"given":"Kenneth M.","family":"Kaufman","sequence":"first","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolan","family":"Linghu","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph D.","family":"Szustakowski","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Husami","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra H.","family":"Filipovich","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ndate","family":"Fall","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Harley","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. 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