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The heterogeneous clinical presentation of Kawasaki disease complicates diagnosis and treatment, highlighting the need for molecular signatures to stratify patients into subgroups to better understand pathogenesis. We performed plasma cell-free RNA sequencing on samples from 98 patients diagnosed with Kawasaki disease, 86 febrile children (62 viral infection, 24 bacterial infection), and 5 healthy children. The Kawasaki disease patients were previously classified into one of four clinical subgroups using 14 clinical variables. Significant differences were observed in cell-free RNA transcript abundance, pathway enrichment scores, and cell type-of-origin fractions, including differences in hepatocyte injury, mitochondrial dysfunction, platelet activation, and developmental markers. This study demonstrates the utility of cell-free RNA to characterize Kawasaki disease subgroups at a molecular level. Cell-free RNA profiles may be used as biomarkers for Kawasaki disease stratification and offer new insight into the pathogenesis of specific KD phenotypes.<\/jats:p>","DOI":"10.1038\/s41598-025-15843-7","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T06:12:12Z","timestamp":1755151932000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular characterization of Kawasaki disease subgroups using cell-free RNA profiling"],"prefix":"10.1038","volume":"15","author":[{"given":"Conor J.","family":"Loy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chisato","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Belcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana H.","family":"Tremoulet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane C.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwijn","family":"De Vlaminck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"issue":"17","key":"15843_CR1","doi-asserted-by":"publisher","first-page":"e927","DOI":"10.1161\/CIR.0000000000000484","volume":"135","author":"BW McCrindle","year":"2017","unstructured":"McCrindle, B. 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