{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T10:12:25Z","timestamp":1780654345299,"version":"3.54.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T00:00:00Z","timestamp":1642982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012326","name":"International Science and Technology Cooperation Programme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Pulmonary atresia (PA) is a kind of congenital heart disease characterized by right ventricular outflow tract obstruction. It is divided into PA with intact ventricular septum (PA\/IVS) whose favorable form is pulmonary valvular stenosis (PS), and PA with ventricular septal defect (PA\/VSD) whose favorable form is tetralogy of Fallot (TOF). Due to limitations in genetics etiology, whole-exome sequencing (WES) was utilized to identify new variants associated with the diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The data from PS-PA\/IVS (<jats:italic>n<\/jats:italic> = 74), TOF-PA\/VSD (<jats:italic>n<\/jats:italic> = 100), and 100 controls were obtained. The common sites between PS and PA\/IVS, PA\/VSD and TOF, were compared. The novel rare damage variants, and candidate genes were identified by gene-based burden analysis. Finally, the enrichment analysis of differential genes was conducted between case and control groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seventeen rare damage variants located in seven genes were predicted to be associated with the PS through burden analysis. Enrichment analysis identified that the Wnt and cadherin signaling pathways were relevant to PS-PA\/IVS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study put forth seven candidate genes (<jats:italic>APC, PPP1R12A, PCK2, SOS2, TNR, MED13<\/jats:italic>, and <jats:italic>TIAM1<\/jats:italic>), resulting in PS-PA\/IVS. The Wnt and cadherin signaling pathways were identified to be related to PS-PA\/IVS by enrichment analysis. This study provides new evidence for exploring the genetic mechanism of PS-PA\/IVS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2021.811156","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T05:09:49Z","timestamp":1643000989000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of Rare Variants in Right Ventricular Outflow Tract Obstruction Congenital Heart Disease by Whole-Exome Sequencing"],"prefix":"10.3389","volume":"8","author":[{"given":"Yue","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hualin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1161\/CIRCRESAHA.116.309140","volume":"120","author":"Zaidi","year":"2017","journal-title":"Circ Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e23333","DOI":"10.1002\/dvg.23333","article-title":"Sheng W, Huang G Functional analysis of rare variants of GATA4 identified in Chinese patients with congenital heart defect","volume":"57","author":"Zhao","year":"2019","journal-title":"Genesis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1007\/s00246-019-02062-x","article-title":"Rare copy number variations might not be involved in the molecular pathogenesis of PA-IVS in an unselected chinese cohort","volume":"40","author":"He","year":"2019","journal-title":"Pediatr Cardiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.ijcard.2018.11.011","article-title":"The outcome of adults born with pulmonary atresia: high morbidity and mortality irrespective of repair","volume":"280","author":"Montanaro","year":"2019","journal-title":"Int J Cardiol."},{"key":"B5","volume-title":"Pulmonary Atresia With Intact Ventricular Septum","author":"Gorla","year":"2020"},{"key":"B6","doi-asserted-by":"publisher","first-page":"S323","DOI":"10.1097\/PCC.0000000000000818","article-title":"Right ventricular outflow tract obstruction: pulmonary atresia with intact ventricular septum, pulmonary stenosis, and ebstein's malformation","volume":"17","author":"Kwiatkowski","year":"2016","journal-title":"Pediatr Crit Care Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1111\/chd.12721","article-title":"Prevalence of Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis","volume":"14","author":"Anderson","year":"2019","journal-title":"Congenit Heart Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.athoracsur.2019.01.046","article-title":"A review of the management of pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries","volume":"108","author":"Soquet","year":"2019","journal-title":"Ann Thorac Surg."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e001690","DOI":"10.1161\/CIRCGENETICS.116.001690","article-title":"Genome-wide association study to find modifiers for tetralogy of fallot in the 22q11.2 deletion syndrome identifies variants in the GPR98 locus on 5q14.3.","volume":"10","author":"Guo","year":"2017","journal-title":"Circ Cardiovasc Genet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1161\/CIRCRESAHA.118.313250","article-title":"Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of fallot","volume":"124","author":"Page","year":"2019","journal-title":"Circ Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1016\/j.jacc.2015.12.032","article-title":"pulmonary valve replacement after repair of pulmonary stenosis compared with tetralogy of fallot","volume":"67","author":"Bokma","year":"2016","journal-title":"J Am Coll Cardiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.echo.2008.11.029","article-title":"Echocardiographic assessment of valve stenosis: EAE\/ASE recommendations for clinical practice","volume":"22","author":"Baumgartner","year":"2009","journal-title":"J Am Soc Echocardiogr"},{"key":"B13","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1002\/uog.19042","article-title":"Clinical application of targeted next-generation sequencing in fetuses with congenital heart defect","volume":"52","author":"Hu","year":"2018","journal-title":"Ultrasound Obstet Gynecol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1093\/cvr\/cvw195","article-title":"Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases","volume":"112","author":"Grunert","year":"2016","journal-title":"Cardiovasc Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1161\/CIRCGENETICS.115.001324","article-title":"Utilization of whole exome sequencing to identify causative mutations in familial congenital heart disease","volume":"9","author":"LaHaye","year":"2016","journal-title":"Circ Cardiovasc Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.csbj.2020.01.011","article-title":"Identification of rare variants in novel candidate genes in pulmonary atresia patients by next generation sequencing","volume":"18","author":"Shi","year":"2020","journal-title":"Comput Struct Biotechnol J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3389\/fgene.2019.00015","article-title":"Sun K, Yu Y Identification of rare copy number variants associated with pulmonary atresia with ventricular septal defect","volume":"10","author":"Xie","year":"2019","journal-title":"Front Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1097\/CRD.0000000000000170","article-title":"Genetic origins of tetralogy of fallot","volume":"26","author":"Morgenthau","year":"2018","journal-title":"Cardiol Rev"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1038\/s41436-020-0757-x","article-title":"The cardiac genome clinic: implementing genome sequencing in pediatric heart disease","volume":"22","author":"Reuter","year":"2020","journal-title":"Genet Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1111\/j.0001-6349.2005.00611.x","article-title":"Association of the C677T methylenetetrahydrofolate reductase mutation with congenital heart diseases","volume":"84","author":"Lee","year":"2005","journal-title":"Acta Obstet Gynecol Scand."},{"key":"B21","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/nature13917","article-title":"Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction","volume":"518","author":"Do","year":"2015","journal-title":"Nature."},{"key":"B22","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1146\/annurev-genom-083115-022609","article-title":"Association tests for rare variants","volume":"17","author":"Nicolae","year":"2016","journal-title":"Annu Rev Genomics Hum Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.devcel.2017.12.001","article-title":"RAPGEF5 regulates nuclear translocation of beta-catenin","volume":"44","author":"Griffin","year":"2018","journal-title":"Dev Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"862","DOI":"10.3389\/fcell.2020.00862","article-title":"The Role of Wnt\/beta-catenin pathway mediators in aortic valve stenosis","volume":"8","author":"Khan","year":"2020","journal-title":"Front Cell Dev Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.ydbio.2015.07.012","article-title":"Sung DC, Butcher JT Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation","volume":"407","author":"Bowen","year":"2015","journal-title":"Dev Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/S0140-6736(18)32042-7","article-title":"Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study","volume":"393","author":"Petrovski","year":"2019","journal-title":"Lancet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1136\/jmedgenet-2015-103018","article-title":"Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome","volume":"52","author":"Yamamoto","year":"2015","journal-title":"J Med Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Tartaglia M, Gelb BD Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"Lancet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1002\/humu.22834","article-title":"Activating mutations affecting the dbl homology domain of SOS2 cause noonan syndrome","volume":"36","author":"Cordeddu","year":"2015","journal-title":"Hum Mutat."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1038\/onc.2011.351","article-title":"Song L, Zhu W Cilia, adenomatous polyposis coli and associated diseases","volume":"31","author":"Li","year":"2012","journal-title":"Oncogene."},{"key":"B31","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1007\/s00395-008-0713-4","article-title":"Genes in congenital heart disease: atrioventricular valve formation","volume":"103","author":"Joziasse","year":"2008","journal-title":"Basic Res Cardiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1161\/CIRCRESAHA.112.275818","article-title":"Myosin phosphatase modulates the cardiac cell fate by regulating the subcellular localization of Nkx25 in a Wnt\/Rho-associated protein kinase-dependent pathway","volume":"112","author":"Ryan","year":"2013","journal-title":"Circ Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1002\/ajmg.a.61734","article-title":"12q21 deletion syndrome: Narrowing the critical region down to 16 Mb including SYT1 and PPP1R12A.","volume":"182","author":"Niclass","year":"2020","journal-title":"Am J Med Genet A."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1007\/s00134-011-2296-z","article-title":"Increased RNA editing in children with cyanotic congenital heart disease","volume":"37","author":"Borik","year":"2011","journal-title":"Intensive Care Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1007\/s00439-013-1407-z","article-title":"Engineered chromosome-based genetic mapping establishes a 37 Mb critical genomic region for Down syndrome-associated heart defects in mice","volume":"133","author":"Liu","year":"2014","journal-title":"Hum Genet."},{"key":"B36","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.ydbio.2020.03.003","article-title":"Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin","volume":"463","author":"Fulmer","year":"2020","journal-title":"Dev Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.yjmcc.2012.04.015","article-title":"A novel player in cellular hypertrophy: Gibetagamma\/PI3K-dependent activation of the RacGEF TIAM-1 is required for alpha(1)-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes","volume":"53","author":"Vettel","year":"2012","journal-title":"J Mol Cell Cardiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1161\/CIRCULATIONAHA.118.037803","article-title":"Lin28a Regulates pathological cardiac hypertrophic growth through Pck2-mediated enhancement of anabolic synthesis","volume":"139","author":"Ma","year":"2019","journal-title":"Circulation."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1002\/stem.3091","article-title":"Mitochondrial phosphoenolpyruvate carboxykinase regulates osteogenic differentiation by modulating AMPK\/ULK1-dependent autophagy","volume":"37","author":"Li","year":"2019","journal-title":"Stem Cells."},{"key":"B40","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1080\/19336918.2015.1008333","article-title":"Transcriptional regulation of tenascin genes","volume":"9","author":"Chiovaro","year":"2015","journal-title":"Cell Adh Migr."},{"key":"B41","doi-asserted-by":"publisher","first-page":"2474","DOI":"10.1046\/j.1460-9568.1999.00670.x","article-title":"Chan BM, Pesheva P Tenascin-R interferes with integrin-dependent oligodendrocyte precursor cell adhesion by a ganglioside-mediated signalling mechanism","volume":"11","author":"Probstmeier","year":"1999","journal-title":"Eur J Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1016\/j.cell.2010.06.011","article-title":"Cell signaling by receptor tyrosine kinases","volume":"141","author":"Lemmon","year":"2010","journal-title":"Cell"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.811156\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T05:09:53Z","timestamp":1643000993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.811156\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,24]]},"references-count":42,"alternative-id":["10.3389\/fcvm.2021.811156"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.811156","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,24]]},"article-number":"811156"}}