{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T18:33:57Z","timestamp":1770489237949,"version":"3.49.0"},"reference-count":88,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008723","name":"Suomen L\u00e4\u00e4ketieteen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100008723","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005744","name":"Lastentautien Tutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100005744","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003125","name":"Suomen Kulttuurirahasto","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100003125","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype\u2013phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development.<\/jats:p>","DOI":"10.3390\/genes12060921","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T10:27:07Z","timestamp":1623839227000},"page":"921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["From Stem Cells to Populations\u2014Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects"],"prefix":"10.3390","volume":"12","author":[{"given":"Martin","family":"Broberg","sequence":"first","affiliation":[{"name":"Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland"},{"name":"Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"H\u00e4stbacka","sequence":"additional","affiliation":[{"name":"New Children\u2019s Hospital, and Pediatric Research Center, Department of Anesthesia and Intensive Care, Helsinki University Hospital, 00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8993-2194","authenticated-orcid":false,"given":"Emmi","family":"Helle","sequence":"additional","affiliation":[{"name":"Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland"},{"name":"New Children\u2019s Hospital, and Pediatric Research Center, Department of Pediatrics, Helsinki University Hospital, 00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.jpeds.2008.05.059","article-title":"Prevalence of Congenital Heart Defects in Metropolitan Atlanta, 1998\u20132005","volume":"153","author":"Reller","year":"2008","journal-title":"J. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/gim.2015.193","article-title":"Cardiovascular Malformations Caused by NOTCH1 Mutations Do Not Keep Left: Data on 428 Probands with Left-Sided CHD and Their Families","volume":"18","author":"Vos","year":"2016","journal-title":"Genet. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1126\/science.281.5373.108","article-title":"Congenital Heart Disease Caused by Mutations in the Transcription Factor NKX2-5","volume":"281","author":"Schott","year":"1998","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1016\/j.jacc.2014.09.048","article-title":"Targeted next-Generation Sequencing Identifies Pathogenic Variants in Familial Congenital Heart Disease","volume":"64","author":"Blue","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1002\/ajmg.a.37108","article-title":"The Diagnostic Value of next Generation Sequencing in Familial Nonsyndromic Congenital Heart Defects","volume":"167A","author":"Jia","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e001978","DOI":"10.1161\/CIRCGEN.117.001978","article-title":"A Screening Approach to Identify Clinically Actionable Variants Causing Congenital Heart Disease in Exome Data","volume":"11","author":"Szot","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nature12141","article-title":"De Novo Mutations in Histone-Modifying Genes in Congenital Heart Disease","volume":"498","author":"Zaidi","year":"2013","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.jacc.2016.11.060","article-title":"Advances in the Genetics of Congenital Heart Disease: A Clinician\u2019s Guide","volume":"69","author":"Blue","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_9","first-page":"151","article-title":"Combined Mutation Screening of NKX2-5, GATA4, and TBX5 in Congenital Heart Disease: Multiple Heterozygosity and Novel Mutations: Multiple Heterozygosity in CHD. Congenit","volume":"7","author":"Pope","year":"2012","journal-title":"Heart Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/gim.2015.60","article-title":"Exome Sequencing Identifies Rare Variants in Multiple Genes in Atrioventricular Septal Defect","volume":"18","author":"Manickaraj","year":"2016","journal-title":"Genet. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e003170","DOI":"10.1161\/CIRCGEN.120.003170","article-title":"Inherited Extremes of Aortic Diameter Confer Risk for a Specific Class of Congenital Heart Disease","volume":"13","author":"Tcheandjieu","year":"2020","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lim, T.B., Foo, S.Y.R., and Chen, C.K. (2021). The Role of Epigenetics in Congenital Heart Disease. Genes, 12.","DOI":"10.3390\/genes12030390"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jpeds.2017.10.046","article-title":"First Trimester Plasma Glucose Values in Women without Diabetes Are Associated with Risk for Congenital Heart Disease in Offspring","volume":"195","author":"Helle","year":"2018","journal-title":"J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1161\/CIRCULATIONAHA.115.017465","article-title":"Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study","volume":"133","author":"Diaz","year":"2016","journal-title":"Circulation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jacc.2018.10.050","article-title":"Maternal Overweight and Obesity and Risk of Congenital Heart Defects","volume":"73","author":"Persson","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4373","DOI":"10.1210\/jc.2013-2831","article-title":"Birth Defects after Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study","volume":"98","author":"Andersen","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e001746","DOI":"10.1161\/CIRCGENETICS.117.001746","article-title":"Genetics of Congenital Heart Disease: Is the Glass Now Half-Full?","volume":"10","author":"Leatherbury","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e002836","DOI":"10.1161\/CIRCGEN.119.002836","article-title":"De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease","volume":"13","author":"Boskovski","year":"2020","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.jtcvs.2015.09.136","article-title":"Burden of Potentially Pathologic Copy Number Variants Is Higher in Children with Isolated Congenital Heart Disease and Significantly Impairs Covariate-Adjusted Transplant-Free Survival","volume":"151","author":"Kim","year":"2016","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nature01827","article-title":"GATA4 Mutations Cause Human Congenital Heart Defects and Reveal an Interaction with TBX5","volume":"424","author":"Garg","year":"2003","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/nature03940","article-title":"Mutations in NOTCH1 Cause Aortic Valve Disease","volume":"437","author":"Garg","year":"2005","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/ng0197-30","article-title":"Mutations in Human TBX5 [corrected] Cause Limb and Cardiac Malformation in Holt-Oram Syndrome","volume":"15","author":"Basson","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1086\/519530","article-title":"Mutations in Cardiac T-Box Factor Gene TBX20 Are Associated with Diverse Cardiac Pathologies, Including Defects of Septation and Valvulogenesis and Cardiomyopathy","volume":"81","author":"Kirk","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nature08516","article-title":"Origins and Functional Impact of Copy Number Variation in the Human Genome","volume":"464","author":"Conrad","year":"2010","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Silversides, C.K., Lionel, A.C., Costain, G., Merico, D., Migita, O., Liu, B., Yuen, T., Rickaby, J., Thiruvahindrapuram, B., and Marshall, C.R. (2012). Rare Copy Number Variations in Adults with Tetralogy of Fallot Implicate Novel Risk Gene Pathways. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002843"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.ajhg.2012.08.003","article-title":"Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease","volume":"91","author":"Soemedi","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ijcard.2015.11.127","article-title":"Genome-Wide Rare Copy Number Variations Contribute to Genetic Risk for Transposition of the Great Arteries","volume":"204","author":"Costain","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1093\/eurheartj\/ehl560","article-title":"Submicroscopic Chromosomal Imbalances Detected by Array-CGH Are a Frequent Cause of Congenital Heart Defects in Selected Patients","volume":"28","author":"Thienpont","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hitz, M.-P., Lemieux-Perreault, L.-P., Marshall, C., Feroz-Zada, Y., Davies, R., Yang, S.W., Lionel, A.C., D\u2019Amours, G., Lemyre, E., and Cullum, R. (2012). Rare Copy Number Variants Contribute to Congenital Left-Sided Heart Disease. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002903"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1093\/bfgp\/elv017","article-title":"The Impact of Human Copy Number Variation on Gene Expression","volume":"14","author":"Gamazon","year":"2015","journal-title":"Brief. Funct. Genom."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/ng.3627","article-title":"Distinct Genetic Architectures for Syndromic and Nonsyndromic Congenital Heart Defects Identified by Exome Sequencing","volume":"48","author":"Sifrim","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1126\/science.aac9396","article-title":"De Novo Mutations in Congenital Heart Disease with Neurodevelopmental and Other Congenital Anomalies","volume":"350","author":"Homsy","year":"2015","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1161\/CIRCULATIONAHA.109.857987","article-title":"Recurrence of Congenital Heart Defects in Families","volume":"120","author":"Poulsen","year":"2009","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1038\/ng.3970","article-title":"Contribution of Rare Inherited and de Novo Variants in 2,871 Congenital Heart Disease Probands","volume":"49","author":"Jin","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13073-017-0482-5","article-title":"Whole Exome Sequencing in 342 Congenital Cardiac Left Sided Lesion Cases Reveals Extensive Genetic Heterogeneity and Complex Inheritance Patterns","volume":"9","author":"Li","year":"2017","journal-title":"Genome Med."},{"key":"ref_36","doi-asserted-by":"crossref","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":"ref_37","doi-asserted-by":"crossref","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":"ref_38","first-page":"1","article-title":"Rapid Whole Genome Sequencing Impacts Care and Resource Utilization in Infants with Congenital Heart Disease","volume":"6","author":"Sweeney","year":"2021","journal-title":"NPJ Genom. Med."},{"key":"ref_39","first-page":"3732","article-title":"Next-Generation Sequencing Identified Genetic Variations in Families with Fetal Non-Syndromic Atrioventricular Septal Defects","volume":"11","author":"Xu","year":"2018","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_40","first-page":"122","article-title":"Recurrence of Discordant Congenital Heart Defects in Families","volume":"2","author":"Poulsen","year":"2010","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/gepi.22176","article-title":"Loss of Function, Missense, and Intronic Variants in NOTCH1 Confer Different Risks for Left Ventricular Outflow Tract Obstructive Heart Defects in Two European Cohorts","volume":"43","author":"Helle","year":"2019","journal-title":"Genet. Epidemiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s41436-018-0260-9","article-title":"Haploinsufficiency of Vascular Endothelial Growth Factor Related Signaling Genes Is Associated with Tetralogy of Fallot","volume":"21","author":"Reuter","year":"2019","journal-title":"Genet. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s41588-020-0652-z","article-title":"Genomic Analyses Implicate Noncoding de Novo Variants in Congenital Heart Disease","volume":"52","author":"Richter","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/humu.22813","article-title":"Comparison of Exome and Genome Sequencing Technologies for the Complete Capture of Protein-Coding Regions","volume":"36","author":"Lelieveld","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_45","doi-asserted-by":"crossref","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":"ref_46","doi-asserted-by":"crossref","first-page":"e002097","DOI":"10.1161\/CIRCGEN.118.002097","article-title":"Beyond Gene Panels: Whole Exome Sequencing for Diagnosis of Congenital Heart Disease","volume":"11","author":"Paige","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/nrg1521","article-title":"Genome-Wide Association Studies for Common Diseases and Complex Traits","volume":"6","author":"Hirschhorn","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1093\/rheumatology\/keu283","article-title":"Impact of Musculoskeletal Pain on Insomnia Onset: A Prospective Cohort Study","volume":"54","author":"Tang","year":"2015","journal-title":"Rheumatology"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Johnston, K.J.A., Adams, M.J., Nicholl, B.I., Ward, J., Strawbridge, R.J., Ferguson, A., McIntosh, A.M., Bailey, M.E.S., and Smith, D.J. (2019). Genome-Wide Association Study of Multisite Chronic Pain in UK Biobank. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008164"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/ng.2636","article-title":"A Genome-Wide Association Study Identifies Two Risk Loci for Congenital Heart Malformations in Han Chinese Populations","volume":"45","author":"Hu","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/ng.2637","article-title":"Genome-Wide Association Study of Multiple Congenital Heart Disease Phenotypes Identifies a Susceptibility Locus for Atrial Septal Defect at Chromosome 4p16","volume":"45","author":"Cordell","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1093\/hmg\/dds552","article-title":"Genome-Wide Association Study Identifies Loci on 12q24 and 13q32 Associated with Tetralogy of Fallot","volume":"22","author":"Cordell","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8082","DOI":"10.1038\/ncomms9082","article-title":"Association Analysis Identifies New Risk Loci for Congenital Heart Disease in Chinese Populations","volume":"6","author":"Lin","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e001449","DOI":"10.1161\/CIRCGENETICS.116.001449","article-title":"Pediatric Cardiac Genomics Consortium* Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects","volume":"10","author":"Agopian","year":"2017","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Lahm, H., Jia, M., Dre\u00dfen, M., Wirth, F., Puluca, N., Gilsbach, R., Keavney, B.D., Cleuziou, J., Beck, N., and Bondareva, O. (2021). Congenital Heart Disease Risk Loci Identified by Genome-Wide Association Study in European Patients. J. Clin. Investig., 131.","DOI":"10.1172\/JCI141837"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Bjornsson, T., Thorolfsdottir, R.B., Sveinbjornsson, G., Sulem, P., Norddahl, G.L., Helgadottir, A., Gretarsdottir, S., Magnusdottir, A., Danielsen, R., and Sigurdsson, E.L. (2018). A Rare Missense Mutation in MYH6 Associates with Non-Syndromic Coarctation of the Aorta. Eur Heart J., 39.","DOI":"10.1101\/180794"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/ije\/dyr178","article-title":"Genome-Wide Significance Project What Should the Genome-Wide Significance Threshold Be? Empirical Replication of Borderline Genetic Associations","volume":"41","author":"Panagiotou","year":"2012","journal-title":"Int. J. Epidemiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1093\/nar\/gkr1255","article-title":"Comprehensive Literature Review and Statistical Considerations for GWAS Meta-Analysis","volume":"40","author":"Begum","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1093\/bioinformatics\/btq340","article-title":"METAL: Fast and Efficient Meta-Analysis of Genomewide Association Scans","volume":"26","author":"Willer","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/gepi.20540","article-title":"Meta-Analysis of Sex-Specific Genome-Wide Association Studies","volume":"34","author":"Magi","year":"2010","journal-title":"Genet. Epidemiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting Meta-Analyses inRwith themetaforPackage","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/ng.572","article-title":"Meta-Analysis and Imputation Refines the Association of 15q25 with Smoking Quantity","volume":"42","author":"Liu","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/stem.2570","article-title":"Concise Review: Induced Pluripotent Stem Cell Research in the Era of Precision Medicine","volume":"35","author":"Hamazaki","year":"2017","journal-title":"Stem Cells"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1007\/s00439-015-1582-1","article-title":"Compound Heterozygous NOTCH1 Mutations Underlie Impaired Cardiogenesis in a Patient with Hypoplastic Left Heart Syndrome","volume":"134","author":"Theis","year":"2015","journal-title":"Hum. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1093\/hmg\/ddx140","article-title":"Induced Pluripotent Stem Cell Modelling of HLHS Underlines the Contribution of Dysfunctional NOTCH Signalling to Impaired Cardiogenesis","volume":"26","author":"Yang","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1002\/stem.2582","article-title":"Wanek Program Genetics Pipeline Group NOTCH1-Dependent Nitric Oxide Signaling Deficiency in Hypoplastic Left Heart Syndrome Revealed Through Patient-Specific Phenotypes Detected in Bioengineered Cardiogenesis","volume":"35","author":"Hrstka","year":"2017","journal-title":"Stem Cells"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.stem.2020.07.015","article-title":"Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome","volume":"27","author":"Miao","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.cell.2015.02.035","article-title":"Human Disease Modeling Reveals Integrated Transcriptional and Epigenetic Mechanisms of NOTCH1 Haploinsufficiency","volume":"160","author":"Theodoris","year":"2015","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1016\/j.cell.2016.11.033","article-title":"Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis","volume":"167","author":"Ang","year":"2016","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e016528","DOI":"10.1161\/JAHA.120.016528","article-title":"Single-Cell Transcriptomics of Engineered Cardiac Tissues from Patient-Specific Induced Pluripotent Stem Cell\u2013Derived Cardiomyocytes Reveals Abnormal Developmental Trajectory and Intrinsic Contractile Defects in Hypoplastic Right Heart Syndrome","volume":"9","author":"Lam","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1161\/CIRCULATIONAHA.112.116996","article-title":"Modeling Supravalvular Aortic Stenosis Syndrome with Human Induced Pluripotent Stem Cells","volume":"126","author":"Ge","year":"2012","journal-title":"Circulation"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2","DOI":"10.5966\/sctm.2012-0054","article-title":"Modeling and Rescue of the Vascular Phenotype of Williams-Beuren Syndrome in Patient Induced Pluripotent Stem Cells","volume":"2","author":"Kinnear","year":"2013","journal-title":"Stem Cells Transl. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"416","DOI":"10.5966\/sctm.2013-0105","article-title":"An Induced Pluripotent Stem Cell Model of Hypoplastic Left Heart Syndrome (HLHS) Reveals Multiple Expression and Functional Differences in HLHS-Derived Cardiac Myocytes","volume":"3","author":"Jiang","year":"2014","journal-title":"Stem Cells Transl. Med."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Kobayashi, J., Yoshida, M., Tarui, S., Hirata, M., Nagai, Y., Kasahara, S., Naruse, K., Ito, H., Sano, S., and Oh, H. (2014). Directed Differentiation of Patient-Specific Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 in Hypoplastic Left Heart Syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0102796"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3389\/fcell.2020.00440","article-title":"Contractility of Induced Pluripotent Stem Cell-Cardiomyocytes with an MYH6 Head Domain Variant Associated With Hypoplastic Left Heart Syndrome","volume":"8","author":"Kim","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1161\/CIRCULATIONAHA.119.045317","article-title":"Patient-Specific Induced Pluripotent Stem Cells Implicate Intrinsic Impaired Contractility in Hypoplastic Left Heart Syndrome","volume":"142","author":"Paige","year":"2020","journal-title":"Circulation"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1124\/pr.116.013003","article-title":"Patient and Disease\u2013Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics","volume":"72","author":"Paik","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.stem.2012.05.005","article-title":"Induced Pluripotent Stem Cells: Past, Present, and Future","volume":"10","author":"Yamanaka","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e99941","DOI":"10.1172\/jci.insight.99941","article-title":"Deep Phenotyping of Human Induced Pluripotent Stem Cell\u2013derived Atrial and Ventricular Cardiomyocytes","volume":"3","author":"Cyganek","year":"2018","journal-title":"JCI Insight"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1161\/CIRCRESAHA.120.316966","article-title":"Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency","volume":"128","author":"Ward","year":"2021","journal-title":"Circ. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e003126","DOI":"10.1161\/CIRCGEN.120.003126","article-title":"Genetic Association Between Hypoplastic Left Heart Syndrome and Cardiomyopathies","volume":"14","author":"Theis","year":"2021","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1152\/physiolgenomics.00091.2016","article-title":"Impact of MYH6 Variants in Hypoplastic Left Heart Syndrome","volume":"48","author":"Stamm","year":"2016","journal-title":"Physiol. Genom."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1007\/s12015-015-9596-6","article-title":"Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as a Model for Heart Development and Congenital Heart Disease","volume":"11","author":"Doyle","year":"2015","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e011541","DOI":"10.1161\/JAHA.119.011541","article-title":"Maternal Obesity and Diabetes Mellitus as Risk Factors for Congenital Heart Disease in the Offspring","volume":"9","author":"Helle","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1161\/CIR.0000000000000352","article-title":"Chronic Heart Failure in Congenital Heart Disease: A Scientific Statement from the American Heart Association","volume":"133","author":"Stout","year":"2016","journal-title":"Circulation"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"596840","DOI":"10.3389\/fped.2020.596840","article-title":"Rare Variants in Genes Associated with Cardiomyopathy Are Not Common in Hypoplastic Left Heart Syndrome Patients with Myocardial Dysfunction","volume":"8","author":"Helle","year":"2020","journal-title":"Front. 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