{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T23:22:16Z","timestamp":1790464936070,"version":"4.1.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T00:00:00Z","timestamp":1654473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"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"}]},{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Patent ductus arteriosus (PDA) is one of the most common congenital heart defects causing pulmonary hypertension, infective endocarditis, and even death. The important role of genetics in determining spontaneous ductal closure has been well-established. However, as many of the identified variants are rare, thorough identification of the associated genetic factors is necessary to further explore the genetic etiology of PDA.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We performed whole-exome sequencing (WES) on 39 isolated nonsyndromic PDA patients and 100 healthy controls. Rare variants and novel genes were identified through bioinformatic filtering strategies. The expression patterns of candidate genes were explored in human embryo heart samples.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Eighteen rare damaging variants of six novel PDA-associated genes (<jats:italic>SOX8<\/jats:italic>, <jats:italic>NES<\/jats:italic>, <jats:italic>CDH2<\/jats:italic>, <jats:italic>ANK3<\/jats:italic>, <jats:italic>EIF4G1<\/jats:italic>, and <jats:italic>HIPK1<\/jats:italic>) were newly identified, which were highly expressed in human embryo hearts.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> WES is an efficient diagnostic tool for exploring the genetic pathogenesis of PDA. These findings contribute new insights into the molecular basis of PDA and may inform further studies on genetic risk factors for congenital heart defects.<\/jats:p>","DOI":"10.3389\/fgene.2022.921925","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T08:33:57Z","timestamp":1654504437000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Rare Variants in Novel Candidate Genes Associated With Nonsyndromic Patent Ductus Arteriosus Identified With Whole-Exome Sequencing"],"prefix":"10.3389","volume":"13","author":[{"given":"Ying","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengjun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3955","DOI":"10.1038\/sj.emboj.7601273","article-title":"Roles of HIPK1 and HIPK2 in AML1- and P300-dependent Transcription, Hematopoiesis and Blood Vessel Formation","volume":"25","author":"Aikawa","year":"2006","journal-title":"EMBO J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.scr.2015.02.002","article-title":"CDH2 and CDH11 Act as Regulators of Stem Cell Fate Decisions","volume":"14","author":"Alimperti","year":"2015","journal-title":"Stem Cell. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cpbi.27","article-title":"Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes","volume":"58","author":"Amberger","year":"2017","journal-title":"Curr. Protoc. Bioinforma."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1542\/peds.2015-3730","article-title":"Patent Ductus Arteriosus in Preterm Infants","volume":"137","author":"Benitz","year":"2016","journal-title":"Pediatrics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1038\/nprot.2008.100","article-title":"Network Analysis Tools: from Biological Networks to Clusters and Pathways","volume":"3","author":"Broh\u00e9e","year":"2008","journal-title":"Nat. Protoc."},{"key":"B6","doi-asserted-by":"publisher","first-page":"24242","DOI":"10.18632\/oncotarget.8168","article-title":"Functional Role of Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) in NSCLC","volume":"7","author":"Cao","year":"2016","journal-title":"Oncotarget"},{"key":"B7","doi-asserted-by":"publisher","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"Fastp: an Ultra-fast All-In-One FASTQ Preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/nmeth.1974","article-title":"The 1000 Genomes Project: Data Management and Community Access","volume":"9","author":"Clarke","year":"2012","journal-title":"Nat. Methods"},{"key":"B9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/chd.12714","article-title":"Molecular and Mechanical Factors Contributing to Ductus Arteriosus Patency and Closure","volume":"14","author":"Crockett","year":"2019","journal-title":"Congenit. Heart Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2947","DOI":"10.1128\/MCB.05589-11","article-title":"Phosphorylation of Eukaryotic Translation Initiation Factor 4G1 (eIF4G1) by Protein Kinase C\u03b1 Regulates eIF4G1 Binding to Mnk1","volume":"31","author":"Dobrikov","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1136\/jmg.2008.058776","article-title":"High Frequency of Submicroscopic Genomic Aberrations Detected by Tiling Path Array Comparative Genome Hybridisation in Patients with Isolated Congenital Heart Disease","volume":"45","author":"Erdogan","year":"2008","journal-title":"J. Med. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1089\/gtmb.2010.0036","article-title":"Using SIFT and PolyPhen to Predict Loss-Of-Function and Gain-Of-Function Mutations","volume":"14","author":"Flanagan","year":"2010","journal-title":"Genet. Test. Mol. Biomarkers"},{"key":"B13","doi-asserted-by":"publisher","first-page":"D945","DOI":"10.1093\/nar\/gkq929","article-title":"COSMIC: Mining Complete Cancer Genomes in the Catalogue of Somatic Mutations in Cancer","volume":"39","author":"Forbes","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"D1049","DOI":"10.1093\/nar\/gku1179","article-title":"Gene Ontology Consortium: Going Forward","volume":"43","author":"Gene Ontology","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1159\/000485354","article-title":"Long Non-coding RNA H19 Protects H9c2 Cells against Hypoxia-Induced Injury by Targeting MicroRNA-139","volume":"44","author":"Gong","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/s41574-019-0224-4","article-title":"Turner Syndrome: Mechanisms and Management","volume":"15","author":"Gravholt","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1210\/jc.2012-2382","article-title":"Klinefelter Syndrome-A Clinical Update","volume":"98","author":"Groth","year":"2013","journal-title":"J. Clin. Endocrinol. Metabolism"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/MCB.00139-18","article-title":"Dynamic Interaction of Eukaryotic Initiation Factor 4G1 (eIF4G1) with eIF4E and eIF1 Underlies Scanning-dependent and -Independent Translation","volume":"38","author":"Haimov","year":"2018","journal-title":"Mol. Cell. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/ejhg.2012.206","article-title":"Incomplete Segregation of MYH11 Variants with Thoracic Aortic Aneurysms and Dissections and Patent Ductus Arteriosus","volume":"21","author":"Harakalova","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"6917","DOI":"10.1093\/nar\/gkz523","article-title":"The SOXE Transcription Factors-SOX8, SOX9 and SOX10-Share a Bi-partite Transactivation Mechanism","volume":"47","author":"Haseeb","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1016\/s0735-1097(02)01886-7","article-title":"The Incidence of Congenital Heart Disease","volume":"39","author":"Hoffman","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New Perspectives on Genomes, Pathways, Diseases and Drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"D840","DOI":"10.1093\/nar\/gkw971","article-title":"The ExAC Browser: Displaying Reference Data Information from over 60 000 Exomes","volume":"45","author":"Karczewski","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"D835","DOI":"10.1093\/nar\/gkz972","article-title":"ClinVar: Improvements to Accessing Data","volume":"48","author":"Landrum","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.biopsych.2012.10.016","article-title":"The ANK3 Bipolar Disorder Gene Regulates Psychiatric-Related Behaviors that Are Modulated by Lithium and Stress","volume":"73","author":"Leussis","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"B26","first-page":"8014","article-title":"CpG Methylation as a Basis for Breast Tumor-specific Loss of NES1\/kallikrein 10 Expression","volume":"61","author":"Li","year":"2001","journal-title":"Cancer Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1016\/j.ajhg.2016.03.022","article-title":"Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus","volume":"98","author":"Li","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.amjms.2019.07.012","article-title":"Discovery of Aberrant Alteration of Genome in Colorectal Cancer by Exome Sequencing","volume":"358","author":"Liang","year":"2019","journal-title":"Am. J. Med. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1054\/bjoc.2001.1870","article-title":"Expression of the Normal Epithelial Cell-specific 1 (NES1; KLK10) Candidate Tumour Suppressor Gene in Normal and Malignant Testicular Tissue","volume":"85","author":"Luo","year":"2001","journal-title":"Br. J. Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1006\/bbrc.1998.8793","article-title":"Structural Characterization and Mapping of the Normal Epithelial Cell-specific 1 Gene","volume":"247","author":"Luo","year":"1998","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2479","DOI":"10.1242\/dev.00465","article-title":"N-cadherin Mediates Retinal Lamination, Maintenance of Forebrain Compartments and Patterning of Retinal Neurites","volume":"130","author":"Masai","year":"2003","journal-title":"Development"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1161\/CIRCGENETICS.116.001605","article-title":"Identification of Cadherin 2 ( CDH2 ) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy","volume":"10","author":"Mayosi","year":"2017","journal-title":"Circ. Cardiovasc Genet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce Framework for Analyzing Next-Generation DNA Sequencing Data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1001\/jama.2018.1896","article-title":"Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen with Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants","volume":"319","author":"Mitra","year":"2018","journal-title":"JAMA"},{"key":"B35","doi-asserted-by":"publisher","first-page":"9137","DOI":"10.1073\/pnas.0402546101","article-title":"A Cardiac Arrhythmia Syndrome Caused by Loss of Ankyrin-B Function","volume":"101","author":"Mohler","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B36","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/s0925-4773(02)00249-6","article-title":"Expression of Sox8, Sox9 and Sox10 in the Developing Valves and Autonomic Nerves of the Embryonic Heart","volume":"118","author":"Montero","year":"2002","journal-title":"Mech. Dev."},{"key":"B37","doi-asserted-by":"publisher","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","article-title":"Reference Sequence (RefSeq) Database at NCBI: Current Status, Taxonomic Expansion, and Functional Annotation","volume":"44","author":"O'Leary","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/329385e0","article-title":"Human Embryo","volume":"329","author":"O'Rahilly","year":"1987","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","first-page":"btv566","DOI":"10.1093\/bioinformatics\/btv566","article-title":"Qualimap 2: Advanced Multi-Sample Quality Control for High-Throughput Sequencing Data","volume":"32","author":"Okonechnikov","year":"2016","journal-title":"Bioinformatics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1002\/humu.23175","article-title":"Structural, Functional, and Clinical Characterization of a NovelPTPN11Mutation Cluster Underlying Noonan Syndrome","volume":"38","author":"Pannone","year":"2017","journal-title":"Hum. Mutat."},{"key":"B41","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1006\/dbio.1996.8443","article-title":"Developmental Defects in Mouse Embryos Lacking N-Cadherin","volume":"181","author":"Radice","year":"1997","journal-title":"Dev. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: a Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/75578","article-title":"Mutations in TFAP2B Cause Char Syndrome, a Familial Form of Patent Ductus Arteriosus","volume":"25","author":"Satoda","year":"2000","journal-title":"Nat. Genet."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e1001527","DOI":"10.1371\/journal.pbio.1001527","article-title":"Transcriptional Corepressors HIPK1 and HIPK2 Control Angiogenesis via TGF-\u03b2-TAK1-dependent Mechanism","volume":"11","author":"Shang","year":"2013","journal-title":"PLoS Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"W446","DOI":"10.1093\/nar\/gkab266","article-title":"MutationTaster2021","volume":"49","author":"Steinhaus","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/s41431-018-0303-3","article-title":"Holt-oram Syndrome: Clinical and Molecular Description of 78 Patients with TBX5 Variants","volume":"27","author":"Vanlerberghe","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional Annotation of Genetic Variants from High-Throughput Sequencing Data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1192\/bjp.bp.114.145433","article-title":"ANK3 Gene Expression in Bipolar Disorder and Schizophrenia","volume":"205","author":"Wirgenes","year":"2014","journal-title":"Br. J. Psychiatry"},{"key":"B49","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1093\/qjmed\/hcy242","article-title":"Kartagener Syndrome","volume":"112","author":"Yang","year":"2019","journal-title":"QJM"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.921925\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T08:34:03Z","timestamp":1654504443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.921925\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,6]]},"references-count":49,"alternative-id":["10.3389\/fgene.2022.921925"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.921925","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,6]]},"article-number":"921925"}}