{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:13:55Z","timestamp":1789154035236,"version":"build-2803163510"},"reference-count":5,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100017759","name":"Childhood Arthritis and Rheumatology Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017759","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012051","name":"Lupus Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000964","name":"Arthritis National Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000964","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\/100000923","name":"Silicon Valley Community Foundation","doi-asserted-by":"publisher","award":["22022\u2010310753"],"award-info":[{"award-number":["22022\u2010310753"]}],"id":[{"id":"10.13039\/100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01NS134358"],"award-info":[{"award-number":["U01NS134358"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002193","name":"Lupus Foundation of America","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002193","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015521","name":"Stanford Maternal and Child Health Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015521","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ACR Open Rheumatology"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Biallelic loss\u2010of\u2010function variants in DNASE1L3 cause inherited systemic lupus erythematosus and hypocomplementemic urticarial vasculitis. These disorders arise from defective clearance of extracellular chromatin, leading to autoantibody formation, immune complex deposition, and complement consumption. The full clinical and therapeutic spectrum of DNASE1L3 deficiency remains incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated a 24\u2010year\u2010old woman with lifelong systemic inflammation characterized by polyarthritis, urticarial vasculitis, episcleritis, recurrent abdominal pain with intestinal angioedema, and persistent hypocomplementemia. Testing included autoantibody profiling, whole\u2010exome sequencing, DNASE1L3 enzymatic assays in cell lysates and supernatants, and plasma analysis of cell\u2010free DNA fragmentation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The patient lacked antinuclear, anti\u2013double\u2010stranded DNA, and anti\u2010Smith antibodies, though antiphospholipid antibodies were intermittently positive. The disease was refractory to multiple immunosuppressive agents but showed partial improvement with JAK inhibition. Genetic analysis revealed compound heterozygous\n                      <jats:italic>DNASE1L3<\/jats:italic>\n                      variants: a pathogenic frameshift (c.290_291delCA) and a novel missense change (c.179T&gt;G, p.Ile60Ser). Functional testing showed markedly impaired DNA degradation for both variants, with residual activity in the missense mutant. Plasma DNA analysis demonstrated reduced mononucleosomal peaks, altered fragment length distribution, and loss of cytosine\u2013cytosine\u2013rich end motifs, confirming reduced nuclease activity in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This case supports the pathogenicity of the DNASE1L3 p.Ile60Ser variant broadening the genetic spectrum. Plasma DNA fragment analysis provides a sensitive biomarker of impaired nuclease function, and JAK inhibition may offer partial therapeutic benefit in DNASE1L3\u2010related systemic inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acr2.70184","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:23:52Z","timestamp":1771806232000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>DNASE1L3<\/scp>\n                    Deficiency With Novel Missense Variant: Enzymatic and Plasma Fragmentomic Evidence of Pathogenicity and Partial Response to\n                    <scp>JAK<\/scp>\n                    Blockade"],"prefix":"10.1002","volume":"8","author":[{"given":"Annel Andrea","family":"Leon Tenorio","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Sugio","sequence":"additional","affiliation":[{"name":"Stanford Cancer Institute, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Stanford Cancer Institute, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon E.","family":"Bonner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University  Stanford California"},{"name":"Stanford Center for Undiagnosed Diseases, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Shahrokh","family":"Esfahani","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine Stanford University  Stanford California"},{"name":"Division of Hematology, Department of Medicine Stanford University  Stanford California"},{"name":"Department of Radiation Oncology Stanford Medicine  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-6371","authenticated-orcid":false,"given":"Sivakanthan","family":"Kasinathan","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce J.","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7831-4224","authenticated-orcid":false,"given":"Amanda","family":"Moyer","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Pediatrics University of Oklahoma Health  Oklahoma City"},{"name":"Arthritis and Clinical Immunology Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Pimentel Vera","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennefer","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University  Stanford California"},{"name":"Stanford Center for Undiagnosed Diseases, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe M.","family":"Reuter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University  Stanford California"},{"name":"Stanford Center for Undiagnosed Diseases, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruti","family":"Marwaha","sequence":"additional","affiliation":[{"name":"Stanford Center for Undiagnosed Diseases, Stanford University  Stanford California"},{"name":"Division of Cardiovascular Medicine, Department of Medicine Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imelda","family":"Balboni","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Stanford Center for Undiagnosed Diseases, Stanford University  Stanford California"},{"name":"Division of Cardiovascular Medicine, Department of Medicine Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University  Stanford California"},{"name":"Stanford Center for Undiagnosed Diseases, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ash","family":"Alizadeh","sequence":"additional","affiliation":[{"name":"Stanford Cancer Institute, Stanford University  Stanford California"},{"name":"Division of Oncology, Department of Medicine Stanford University  Stanford California"},{"name":"Division of Hematology, Department of Medicine Stanford University  Stanford California"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6740-1154","authenticated-orcid":false,"given":"Natalia","family":"Gomez\u2010Ospina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Stanford University  Stanford California"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University  Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.06.069"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.975"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38010"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.09.006"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2024.05.014"}],"container-title":["ACR Open Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acr2.70184","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acr2.70184","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acr2.70184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T15:49:34Z","timestamp":1772984974000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/acr2.70184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":5,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/acr2.70184"],"URL":"https:\/\/doi.org\/10.1002\/acr2.70184","archive":["Portico"],"relation":{},"ISSN":["2578-5745","2578-5745"],"issn-type":[{"value":"2578-5745","type":"print"},{"value":"2578-5745","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]},"assertion":[{"value":"2025-11-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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