{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:05:05Z","timestamp":1784613905537,"version":"3.55.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"\n Background<\/jats:title>\n Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Previous reports in the United States have suggested that TA-TMA is caused by complement-related genetic variants. However, these findings need to be validated in other countries and ethnic populations.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We performed targeted sequencing of 40 complement-and coagulopathy-related genes in 44 Japanese pediatric patients who underwent HSCT, including 20 patients with TA-TMA and 24 patients without TA-TMA. Seventeen genes reported to be related to TA-TMA were included. Additionally, 23 genes that are thought to be associated with complement system activation and coagulopathy were investigated.\n CFHR<\/jats:italic>\n 1\n \/CFHR<\/jats:italic>\n 3 deletions were also examined using multiplex ligation-dependent probe amplification.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n There was no significant difference in the percentage of patients bearing genetic variants between patients with and without TA-TMA. Furthermore, no marked differences in the percentage of patients or the average number of rare variants per patient were found between the two groups. Although we identified several rare non-synonymous variants in TA-TMA patients, we did not find any known pathogenic variants causing TA-TMA. Interestingly, a novel rare genetic variant in the\n C<\/jats:italic>\n 1\n r-like protein (C<\/jats:italic>\n 1\n RL)<\/jats:italic>\n gene was identified in a patient with neuroblastoma who had undergone autologous HSCT, potentially associated with TA-TMA.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n In this limited number of Japanese pediatric cohort with TA-TMA, we could not find an enrichment of rare variants among 40 complement- and coagulopathy-related genes. A novel, rare variant of\n C<\/jats:italic>\n 1\n RL<\/jats:italic>\n was identified in a single patient with TA-TMA. Further studies with larger cohorts are necessary to clarify the genetic association in Japanese patients with TA-TMA.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fped.2026.1879540","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:35:16Z","timestamp":1784612116000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Complement-related genetic analysis for Japanese children with transplant-associated thrombotic microangiopathy"],"prefix":"10.3389","volume":"14","author":[{"given":"Ai","family":"Yamada","sequence":"first","affiliation":[{"name":"Division of Pediatrics, Faculty of Medicine, University of Miyazaki","place":["Miyazaki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Nagasawa","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Faculty of Medicine, University of Miyazaki","place":["Miyazaki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midori","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Faculty of Medicine, University of Miyazaki","place":["Miyazaki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiyo","family":"Kamimura","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Faculty of Medicine, University of Miyazaki","place":["Miyazaki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kindai University Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, National Hospital Organization Kyushu Cancer Center","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiichiro","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, Hyogo Prefectural Kobe Children\u2019s Hospital","place":["Hyogo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kagoshima University School of Medical and Dental Science","place":["Kagoshima, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanobu","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yokohama City University Hospital","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Ohara","sequence":"additional","affiliation":[{"name":"Department of Applied Genomics, Kazusa DNA Research Institute","place":["Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Moritake","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Faculty of Medicine, University of Miyazaki","place":["Miyazaki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1053\/j.seminhematol.2011.10.008","article-title":"Chronic kidney diseases in long-term survivors after allogeneic hematopoietic stem cell transplantation: monitoring and management guidelines","volume":"49","author":"Abboud","year":"2012","journal-title":"Semin Hematol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.pcl.2013.02.007","article-title":"Advances in critical care of the pediatric hematopoietic stem cell transplant patient","volume":"60","author":"Chima","year":"2013","journal-title":"Pediatr Clin North Am"},{"key":"B3","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.blre.2014.11.001","article-title":"A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury","volume":"29","author":"Jodele","year":"2015","journal-title":"Blood Rev"},{"key":"B4","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.ejim.2013.05.009","article-title":"Complement activation in diseases presenting with thrombotic microangiopathy","volume":"24","author":"Meri","year":"2013","journal-title":"Eur J Intern Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1997","DOI":"10.1182\/blood-2013-07-512707","article-title":"TMA: beware of complements","volume":"122","author":"Ricklin","year":"2013","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1182\/blood-2011-02-321315","article-title":"Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy","volume":"118","author":"Laskin","year":"2011","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1097\/TP.0b013e3181f24e8d","article-title":"Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation","volume":"90","author":"Cho","year":"2010","journal-title":"Transplantation"},{"key":"B8","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1038\/bmt.2017.207","article-title":"Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies","volume":"53","author":"Khosla","year":"2018","journal-title":"Bone Marrow Transplant"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1182\/blood-2013-05-501445","article-title":"Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy","volume":"122","author":"Jodele","year":"2013","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1182\/blood-2014-03-564997","article-title":"Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults","volume":"124","author":"Jodele","year":"2014","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1182\/blood.2019004218","article-title":"Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab","volume":"135","author":"Jodele","year":"2020","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1182\/blood.2023022526","article-title":"A prospective multi-institutional study of eculizumab to treat high-risk stem cell transplantation-associated TMA","volume":"143","author":"Jodele","year":"2024","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1182\/blood-2015-08-663435","article-title":"The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy","volume":"127","author":"Jodele","year":"2016","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jtct.2022.11.015","article-title":"Harmonizing definitions for diagnostic criteria and prognostic assessment of transplantation-associated thrombotic microangiopathy: a report on behalf of the European society for blood and marrow transplantation, American society for transplantation and cellular therapy, Asia-Pacific blood and marrow transplantation group, and center for international blood and marrow transplant research","volume":"29","author":"Schoettler","year":"2023","journal-title":"Transplant Cell Ther"},{"key":"B15","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/j.jmoldx.2018.04.004","article-title":"Assessing the accuracy of variant detection in cost-effective gene panel testing by next-generation sequencing","volume":"20","author":"Fujiki","year":"2018","journal-title":"J Mol Diagn"},{"key":"B16","doi-asserted-by":"publisher","first-page":"847","DOI":"10.7150\/jca.66177","article-title":"Rutaecarpine suppresses the proliferation and metastasis of colon cancer cells by regulating the STAT3 signaling","volume":"13","author":"Chan","year":"2022","journal-title":"J Cancer"},{"key":"B17","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.bbrc.2004.06.127","article-title":"A novel human dendritic cell-derived C1r-like serine protease analog inhibits complement-mediated cytotoxicity","volume":"321","author":"Lin","year":"2004","journal-title":"Biochem Biophys Res Commun"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2536","DOI":"10.1182\/bloodadvances.2019001242","article-title":"Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort","volume":"4","author":"Schoettler","year":"2020","journal-title":"Blood Adv"},{"key":"B19","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.amjms.2016.05.003","article-title":"The alternative pathway of complement and the evolving clinical-pathophysiological spectrum of atypical hemolytic uremic syndrome","volume":"352","author":"Berger","year":"2016","journal-title":"Am J Med Sci"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1007\/s40620-025-02359-6","article-title":"Atypical hemolytic uremic syndrome is not always complement mediated: lesson for the clinical nephrologist","volume":"38","author":"Spasiano","year":"2025","journal-title":"J Nephrol"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1879540\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:35:17Z","timestamp":1784612117000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1879540\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":20,"alternative-id":["10.3389\/fped.2026.1879540"],"URL":"https:\/\/doi.org\/10.3389\/fped.2026.1879540","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"article-number":"1879540"}}