{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T03:01:41Z","timestamp":1789527701725,"version":"build-2803163510"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100005150","name":"Chinese Academy of Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005150","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Initiative for Innovative Medicine","award":["2016-I2M-1-016"],"award-info":[{"award-number":["2016-I2M-1-016"]}]},{"DOI":"10.13039\/501100010909","name":"Young Scientists Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010909","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31801103"],"award-info":[{"award-number":["31801103"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Anomalous pulmonary venous return (APVR) is a potentially lethal congenital heart disease. Elucidating the genetic etiology is crucial for understanding its pathogenesis and improving clinical practice, whereas its genetic basis remains largely unknown because of complex genetic etiology. We thus performed whole-exome sequencing for 144 APVR patients and 1636 healthy controls and report a comprehensive atlas of APVR-related rare genetic variants. Novel singleton, loss-of-function and deleterious missense variants (DVars) were enriched in patients, particularly for genes highly expressed in the developing human heart at the critical time point for pulmonary veins draining into the left atrium. Notably, PLXND1, encoding a receptor for semaphorins, represents a strong candidate gene of APVR (adjusted P\u2009=\u20091.1e-03, odds ratio: 10.9\u201369.3), accounting for 4.17% of APVR. We further validated this finding in an independent cohort consisting of 82 case\u2013control pairs. In these two cohorts, eight DVars were identified in different patients, which convergently disrupt the GTPase-activating protein-related domain of PLXND1. All variant carriers displayed strikingly similar clinical features, in that all anomalous drainage of pulmonary vein(s) occurred on the right side and incorrectly connected to the right atrium, which may represent a novel subtype of APVR for molecular diagnosis. Studies in Plxnd1 knockout mice further revealed the effects of PLXND1 deficiency on severe heart and lung defects and cellular abnormalities related to APVR such as abnormal migration and vascular formation of vascular endothelial cells. These findings indicate the important role of PLXND1 in APVR pathogenesis, providing novel insights into the genetic etiology and molecular subtyping for APVR.<\/jats:p>","DOI":"10.1093\/hmg\/ddab331","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T20:14:41Z","timestamp":1636488881000},"page":"1443-1452","source":"Crossref","is-referenced-by-count":4,"title":["Association of <i>PLXND1<\/i> with a novel subtype of anomalous pulmonary venous return"],"prefix":"10.1093","volume":"31","author":[{"given":"Wei-Zhen","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Zeng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"},{"name":"Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huayan","family":"Shen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjiao","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baihui","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfang","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujing","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenke","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianmei","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Megagenomics Corporation, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Megagenomics Corporation, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshuang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Megagenomics Corporation, Beijing 100875, China"},{"name":"Department of Public Health Intelligence, Ping An Healthcare Technology, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Jing","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Echocardiography, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou-Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Pediatric Cardiac Surgery Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7674-9857","authenticated-orcid":false,"given":"Zhou","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"2022050521130091600_ref1","first-page":"e29","article-title":"Heart disease and stroke statistics--2015 update: a report from the American Heart Association","volume":"131","author":"Mozaffarian","year":"2015","journal-title":"Circulation"},{"key":"2022050521130091600_ref2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1161\/CIRCULATIONAHA.115.019307","article-title":"Congenital heart defects in the United States: estimating the magnitude of the affected population in 2010","volume":"134","author":"Gilboa","year":"2016","journal-title":"Circulation"},{"key":"2022050521130091600_ref3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jpeds.2018.08.040","article-title":"Prevalence of congenital heart disease at live birth in China","volume":"204","author":"Zhao","year":"2019","journal-title":"J. Pediatr."},{"key":"2022050521130091600_ref4","doi-asserted-by":"crossref","first-page":"e1502","DOI":"10.1542\/peds.2012-3435","article-title":"Temporal trends in survival among infants with critical congenital heart defects","volume":"131","author":"Oster","year":"2013","journal-title":"Pediatrics"},{"key":"2022050521130091600_ref5","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.amjcard.2016.05.056","article-title":"Health care costs for adults with congenital heart disease in the United States 2002 to 2012","volume":"118","author":"Briston","year":"2016","journal-title":"Am. J. Cardiol."},{"key":"2022050521130091600_ref6","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/RTI.0b013e318194c942","article-title":"MDCT of partial anomalous pulmonary venous return (PAPVR) in adults","volume":"24","author":"Ho","year":"2009","journal-title":"J. Thorac. Imaging"},{"key":"2022050521130091600_ref7","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/ije\/dyz009","article-title":"Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies","volume":"48","author":"Liu","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"2022050521130091600_ref8","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1017\/S1047951101000993","article-title":"Development of the human pulmonary vein and its incorporation in the morphologically left atrium","volume":"11","author":"Webb","year":"2001","journal-title":"Cardiol. Young"},{"key":"2022050521130091600_ref9","doi-asserted-by":"crossref","first-page":"e22055","DOI":"10.1371\/journal.pone.0022055","article-title":"Development of the pulmonary vein and the systemic venous sinus: an interactive 3D overview","volume":"6","author":"Berg","year":"2011","journal-title":"PLoS One"},{"key":"2022050521130091600_ref10","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1093\/cvr\/cvx188","article-title":"CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries","volume":"113","author":"Kim","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"2022050521130091600_ref11","doi-asserted-by":"crossref","first-page":"17971","DOI":"10.1074\/jbc.M113.544833","article-title":"Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways","volume":"289","author":"Aghajanian","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2022050521130091600_ref12","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/nm.3185","article-title":"Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections","volume":"19","author":"Degenhardt","year":"2013","journal-title":"Nat. Med."},{"key":"2022050521130091600_ref13","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1093\/hmg\/ddq005","article-title":"Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms","volume":"19","author":"Bleyl","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2022050521130091600_ref14","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/humu.20711","article-title":"Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return","volume":"29","author":"Cinquetti","year":"2008","journal-title":"Hum. Mutat."},{"key":"2022050521130091600_ref15","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.ebiom.2018.11.008","article-title":"Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection","volume":"38","author":"Shi","year":"2018","journal-title":"EBioMedicine"},{"key":"2022050521130091600_ref16","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/ar.23909","article-title":"A novel mouse model for cilia-associated cardiovascular anomalies with a high penetrance of total anomalous pulmonary venous return","volume":"302","author":"Burns","year":"2019","journal-title":"Anat. Rec."},{"key":"2022050521130091600_ref17","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1177\/2150135117708706","article-title":"Persistent left superior vena cava: incidence and management in patients undergoing repair of partial anomalous pulmonary venous connection","volume":"8","author":"Clarke","year":"2017","journal-title":"World J. Pediatr. Congenit. Heart Surg."},{"key":"2022050521130091600_ref18","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1093\/ejcts\/ezt098","article-title":"The developing pulmonary veins and left atrium: implications for ablation strategy for atrial fibrillation","volume":"44","author":"Sherif","year":"2013","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"2022050521130091600_ref19","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1016\/j.cell.2019.11.025","article-title":"A spatiotemporal organ-wide gene expression and cell atlas of the developing human heart","volume":"179","author":"Asp","year":"2019","journal-title":"Cell"},{"key":"2022050521130091600_ref20","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"2022050521130091600_ref21","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1073\/pnas.1308418111","article-title":"Genetic dissection of plexin signaling in vivo","volume":"111","author":"Worzfeld","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2022050521130091600_ref22","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.pbiomolbio.2015.03.006","article-title":"Structural mechanisms of plexin signaling","volume":"118","author":"Pascoe","year":"2015","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"2022050521130091600_ref23","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.devcel.2004.06.002","article-title":"PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development","volume":"7","author":"Gitler","year":"2004","journal-title":"Dev. Cell"},{"key":"2022050521130091600_ref24","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.yexcr.2013.02.003","article-title":"The role of semaphorins and their receptors in vascular development and cancer","volume":"319","author":"Gu","year":"2013","journal-title":"Exp. Cell Res."},{"key":"2022050521130091600_ref25","doi-asserted-by":"crossref","first-page":"e008853","DOI":"10.1161\/JAHA.118.008853","article-title":"Role of Semaphorin Signaling during cardiovascular development","volume":"7","author":"Sun","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"2022050521130091600_ref26","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ydbio.2008.09.031","article-title":"Tie2Cre-mediated inactivation of plexinD1 results in congenital heart, vascular and skeletal defects","volume":"325","author":"Zhang","year":"2009","journal-title":"Dev. Biol."},{"key":"2022050521130091600_ref27","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1152\/physiolgenomics.00033.2003","article-title":"Developmental anatomy of the heart: a tale of mice and man","volume":"15","author":"Wessels","year":"2003","journal-title":"Physiol. Genomics"},{"key":"2022050521130091600_ref28","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1093\/eurheartj\/ehx314","article-title":"Familial co-occurrence of congenital heart defects follows distinct patterns","volume":"39","author":"Ellesoe","year":"2018","journal-title":"Eur. Heart J."},{"key":"2022050521130091600_ref29","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1002\/ajmg.a.36194","article-title":"Isolated truncus arteriosus associated with a mutation in the plexin-D1 gene","volume":"161A","author":"Ta-Shma","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"2022050521130091600_ref30","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1016\/j.celrep.2019.01.079","article-title":"Single-cell transcriptome analysis maps the developmental track of the human heart","volume":"26","author":"Cui","year":"2019","journal-title":"Cell Rep."},{"key":"2022050521130091600_ref31","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41586-020-2922-4","article-title":"A molecular cell atlas of the human lung from single-cell RNA sequencing","volume":"587","author":"Travaglini","year":"2020","journal-title":"Nature"},{"key":"2022050521130091600_ref32","article-title":"Genetics of congenital heart disease","volume":"9","author":"Williams","year":"2019","journal-title":"Biomol. Ther."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab331\/41988302\/ddab331.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/9\/1443\/43546613\/ddab331.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/9\/1443\/43546613\/ddab331.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T21:20:56Z","timestamp":1651785656000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/9\/1443\/6428120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,11,15]]},"published-print":{"date-parts":[[2022,5,4]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab331","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,5,1]]},"published":{"date-parts":[[2021,11,15]]}}}