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Recently, we identified four computable phenotypes showing distinct cytokine profiles, clinical outcomes, and therapeutic response characteristics (PedSep-A, B, C, and D) in a multicenter pediatric sepsis cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In the cohort data, we collected whole-exome sequencing data and identified rare variants associated with PedSep-D phenotype by conducting a gene-based analysis in an aggregated fashion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      As a result, one whole-exome significant gene (\n                      <jats:italic>LTBP4<\/jats:italic>\n                      ) and two suggestive significant genes (\n                      <jats:italic>PLA2G4E<\/jats:italic>\n                      ,\n                      <jats:italic>CCDC157<\/jats:italic>\n                      ) showed association with PedSep-D, the phenotype characterized by the most severe outcomes and highest inflammation. The associated variants in\n                      <jats:italic>LTBP4<\/jats:italic>\n                      were enriched for predicted deleterious effects based on established functional prediction metrics. All three associated genes are implicated in inflammation and immune cell activation based on existing gene function and expression data. Although the circulating cytokine profiles were overlapping between the rare variant carriers, we also identified gene-specific cytokine changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Altogether, our study provides valuable insights into the genetic architecture of a pediatric sepsis phenotype with the highest inflammation level and the most severe outcomes, highlighting potential candidate genes and pathways for further biomarker and therapeutic studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Impact<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Pediatric sepsis exhibits substantial heterogeneity, with genetic variation contributing to this variability. Rare variants in LTBP4 are significantly associated with the most severe pediatric sepsis phenotype (PedSep-D), while variants in PLA2G4E and CCDC157 show associations with this phenotype in suggestive significance.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Expands on the concept of sepsis phenotypes (PedSep-A, B, C, D) by incorporating genetic insights, moving beyond clinical and cytokine profiles to uncover molecular drivers.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Opens new avenues for mechanistic studies to understand the genetic underpinnings of severe inflammation and immune activation in sepsis.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41390-025-04420-3","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:35:51Z","timestamp":1760178951000},"page":"2007-2018","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deleterious variants in LTBP4 are associated with severe pediatric sepsis"],"prefix":"10.1038","volume":"99","author":[{"given":"Yidi","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate F.","family":"Kernan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Shaffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Urban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Canna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray M.","family":"Pollack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Meert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Newth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Shanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick E.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A.","family":"Carcillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Jung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,11]]},"reference":[{"key":"4420_CR1","unstructured":"World Health Organisation. 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Drs. Carcillo\u2019s, Berg\u2019s, Wessel\u2019s, Pollack\u2019s, Meert\u2019s, Hall\u2019s, Doctor\u2019s, Cornell\u2019s, Harrison\u2019s, Zuppa\u2019s, Reeder\u2019s, Banks\u2019s, and Holubkov\u2019s institutions received funding from the National Institutes of Health (NIH). Drs. Carcillo\u2019s, Newth\u2019s, Shanley\u2019s, and Dean\u2019s institutions received funding from the National Institutes of Child Health and Human Development. Drs. Carcillo, Berg, Wessel, Polack, Meert, Hall, Newth, Doctor, Shanley, Cornell, Harrison, Zuppa, Reeder, Banks, Holubkov, Notterman, and Dean received support for article research from the NIH. Dr. Carcillo\u2019s institution also received funding from the National Institutes of General Medical Sciences. Dr. Pollack disclosed that his research is supported by philanthropy from Mallinckrodt Pharmaceuticals. Dr. Hall received funding from Bristol Myers-Squibb (for service on an advisory board) and LaJolla Pharmaceuticals (service as a consultant), both unrelated to the current submission. Dr. Newth received funding from Philips Research North America. Dr. Doctor\u2019s institution received funding from the Department of Defense and Kalocyte. Dr. Shanley received funding from Springer publishing, International Pediatric Research Foundation, and Pediatric Academic Societies. Dr. Cornell disclosed he is co-founder of Pre-Dixon Bio. Dr. Holubkov received funding from Pfizer (Data Safety Monitoring Board [DSMB] member), Medimmune (DSMB member), Physicians Committee for Responsible Medicine (biostatistical consulting), DURECT Corporation (biostatistical consulting), Armaron Bio (DSMB past member), and St Jude Medical (DSMB past member). The remaining authors have disclosed that they do not have any potential competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was approved by the Institutional Review Board at University of Utah Central IRB # 70976.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent statement"}}]}}