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Severe sporadic disease in children is often explained by \u201cde novo\u201d variants that can be uncovered by trio sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole\u2010exome sequencing was performed in 50 Chinese trios with childhood\u2010onset SLE (cSLE). Rare coding variants in SLE\u2010associated genes and all de novo variants were investigated. Gene pathway and expression analysis and interferon\u2010\u03b2 (IFN\u03b2) luciferase assays were used to predict contribution to disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Each proband carried at least one rare variant in an SLE\u2010associated gene, with a median of six per child. At least two probands had monogenic disease, and one\u2010third of probands carried novel or rare variants in genes well accepted to cause monogenic SLE:\n                      <jats:italic>ACP5<\/jats:italic>\n                      ,\n                      <jats:italic>C3<\/jats:italic>\n                      ,\n                      <jats:italic>C4A<\/jats:italic>\n                      ,\n                      <jats:italic>C4B<\/jats:italic>\n                      ,\n                      <jats:italic>DNASE1<\/jats:italic>\n                      ,\n                      <jats:italic>IFIH1<\/jats:italic>\n                      ,\n                      <jats:italic>NRAS<\/jats:italic>\n                      ,\n                      <jats:italic>RNASEH2B<\/jats:italic>\n                      ,\n                      <jats:italic>RNASEH2C<\/jats:italic>\n                      , and\n                      <jats:italic>SAMHD1<\/jats:italic>\n                      . Probands carried a median of one de novo, rare, coding variant. Intriguingly, although only two de novo variants occurred in genes previously associated with SLE, 12 of the 50 genes were enriched in the top 20 SLE\u2010related pathways and were highly expressed in age\u2010associated B cells and plasma B cells. These genes represent promising candidate lupus genes. Two de novo variants occurring in genes not previously linked to SLE or autoimmunity,\n                      <jats:italic>DHX8<\/jats:italic>\n                      and\n                      <jats:italic>ACTR5<\/jats:italic>\n                      , enhanced type I IFN signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study highlights the abundance of lupus\u2010relevant rare gene variants in cSLE, supports frequent contribution of de novo variants to disease, and identifies genes that may constitute novel therapeutic targets of relevance to Chinese patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.43243","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T06:36:01Z","timestamp":1747636561000},"page":"1548-1559","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Trio Whole Exome Sequencing in Chinese Childhood\u2010Onset Lupus Reveals Novel Candidate Genes"],"prefix":"10.1002","volume":"77","author":[{"given":"Jianyang","family":"Ma","sequence":"first","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology and Shanghai Institute of Rheumatology School of Medicine, Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Qin","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology and Shanghai Institute of Rheumatology School of Medicine, Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soon\u2010Min","family":"Hong","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Rheumatology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuvaraka","family":"Ware","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute  London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Hou","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Rheumatology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Tan","sequence":"additional","affiliation":[{"name":"Division of Immunology and Infectious Disease John Curtin School of Medical Research, The Australian National University  Canberra Australian Capital Territory Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengmei","family":"Xie","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology and Shanghai Institute of Rheumatology School of Medicine, Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology and Shanghai Institute of Rheumatology School of Medicine, Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Wu","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology and Shanghai Institute of Rheumatology School of Medicine, Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todor","family":"Arsov","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences Goce Delcev University  Shtip North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanfang","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Renji Hospital, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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