{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:15:51Z","timestamp":1784546151547,"version":"3.55.0"},"reference-count":17,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,5,2]],"date-time":"2018-05-02T00:00:00Z","timestamp":1525219200000},"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":["R01\u2010AR\u2010059049"],"award-info":[{"award-number":["R01\u2010AR\u2010059049"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010327","name":"Cincinnati Children\u2019s Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010327","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002136","name":"Histiocytosis Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002136","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Macrophage activation syndrome (MAS) is a life\u2010threatening complication of systemic juvenile idiopathic arthritis (JIA) and has pathologic similarity to hemophagocytic lymphohistiocytosis (HLH). Intronic variants in <jats:italic>UNC13D<\/jats:italic> are found in patients with familial HLH type 3 (FHLH3), but the role of noncoding variants in MAS is unknown. The objective of this study was to identify deep intronic <jats:italic>UNC13D<\/jats:italic> variants in patients with MAS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A custom enrichment library was constructed to sequence a genomic region of ~1 Mb flanking <jats:italic>UNC13D<\/jats:italic> in 24 patients with systemic JIA, recurrent MAS, and negative results of prior genetic (exon\/coding) testing. The functional consequences of intronic variants were assessed using quantitative polymerase chain reaction in patient\u2010derived peripheral blood mononuclear cells (PBMCs), electromobility shift assay, in vitro transcriptional enhancer assays, and natural killer (NK) cell degranulation assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We evaluated a patient with systemic JIA and recurrent MAS in whom a novel functional intronic variant in <jats:italic>UNC13D<\/jats:italic>, c.117+143A&gt;G, was observed. This variant occurred in a proposed regulatory region that drives lymphocyte\u2010specific <jats:italic>UNC13D<\/jats:italic> expression and is associated with reduced transcript levels in patient PBMCs. This variant also disrupted NF\u2010\u03baB binding to a functional transcriptional enhancer, leading to reduced enhancer activity in vitro. Partial knockdown of <jats:italic>UNC13D<\/jats:italic> expression also led to impaired NK cell degranulation. An additional patient was identified with a previously described <jats:italic>UNC13D<\/jats:italic> intronic variant, for a total noncoding variant hit rate of 8.3% (2 of 24).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings highlight the notion that intronic variants in key regulatory regions may be associated with MAS in patients with systemic JIA and support deep sequencing approaches when causative coding variants are not identified.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40438","type":"journal-article","created":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T16:26:44Z","timestamp":1517934404000},"page":"963-970","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Brief Report: Novel <i>UNC13D<\/i> Intronic Variant Disrupting an NF\u2010\u03baB Enhancer in a Patient With Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"Grant S.","family":"Schulert","sequence":"first","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingce","family":"Zhang","sequence":"additional","affiliation":[{"name":"Children's Hospital of Alabama University of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Husami","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ndate","family":"Fall","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermine","family":"Brunner","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy Q.","family":"Cron","sequence":"additional","affiliation":[{"name":"Children's Hospital of Alabama University of Alabama at Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei A.","family":"Grom","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2012.3"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23734"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38793"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-014-0439-2"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24955"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-369090"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12371"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131131"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34604"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103129"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501284"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21039"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39332"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep418"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv550"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.121233"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.3.1786"}],"container-title":["Arthritis &amp; 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