{"PubmedArticle":{"MedlineCitation":{"@attributes":{"Status":"MEDLINE","Owner":"NLM","IndexingMethod":"Curated"},"PMID":{"@attributes":{"Version":"1"},"@text":"38570875"},"DateCompleted":{"Year":"2024","Month":"04","Day":"05"},"DateRevised":{"Year":"2026","Month":"01","Day":"27"},"Article":{"@attributes":{"PubModel":"Electronic"},"Journal":{"ISSN":{"@attributes":{"IssnType":"Electronic"},"@text":"1756-994X"},"JournalIssue":{"@attributes":{"CitedMedium":"Internet"},"Volume":"16","Issue":"1","PubDate":{"Year":"2024","Month":"Apr","Day":"03"}},"Title":"Genome medicine","ISOAbbreviation":"Genome Med"},"ArticleTitle":"NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy.","Pagination":{"StartPage":"53","MedlinePgn":"53"},"ELocationID":[{"@attributes":{"EIdType":"pii","ValidYN":"Y"},"@text":"53"},{"@attributes":{"EIdType":"doi","ValidYN":"Y"},"@text":"10.1186\/s13073-024-01312-9"}],"Abstract":{"AbstractText":[{"@attributes":{"Label":"BACKGROUND"},"@text":"NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-\u03b2\/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects."},{"@attributes":{"Label":"METHODS"},"@text":"We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with known NODAL variants and CHD from institutional research and clinical cohorts to investigate an allelic series. For those with candidate contributory variants, variant allele confirmation and segregation analysis were studied by Sanger sequencing in available family members. Array comparative genomic hybridization and droplet digital PCR were utilized for copy number variants (CNV) validation and characterization. We performed Human Phenotype Ontology (HPO)-based quantitative phenotypic analyses to dissect allele-specific phenotypic differences."},{"@attributes":{"Label":"RESULTS"},"@text":"Missense, nonsense, splice site, indels, and\/or structural variants of NODAL were identified as potential causes of heterotaxy and other laterality defects in 33 CHD cases. We describe a recurrent complex indel variant for which the nucleic acid secondary structure predictions implicate secondary structure mutagenesis as a possible mechanism for formation. We identified two CNV deletion alleles spanning NODAL in two unrelated CHD cases. Furthermore, 17 CHD individuals were found (16\/17 with known Hispanic ancestry) to have the c.778G\u2009>\u2009A:p.G260R NODAL missense variant which we propose reclassification from variant of uncertain significance (VUS) to likely pathogenic. Quantitative HPO-based analyses of the observed clinical phenotype for all cases with p.G260R variation, including heterozygous, homozygous, and compound heterozygous cases, reveal clustering of individuals with biallelic variation. This finding provides evidence for a genotypic-phenotypic correlation and an allele-specific gene dosage model."},{"@attributes":{"Label":"CONCLUSION"},"@text":"Our data further support a role for rare deleterious variants in NODAL as a cause for sporadic human laterality defects, expand the repertoire of observed anatomical complexity of potential cardiovascular anomalies, and implicate an allele specific gene dosage model."}],"CopyrightInformation":"\u00a9 2024. The Author(s)."},"AuthorList":{"@attributes":{"CompleteYN":"Y"},"Author":[{"@attributes":{"ValidYN":"Y","EqualContrib":"Y"},"LastName":"Dardas","ForeName":"Zain","Initials":"Z","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0003-2387-3122"}],"AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y","EqualContrib":"Y"},"LastName":"Fatih","ForeName":"Jawid M","Initials":"JM","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y","EqualContrib":"Y"},"LastName":"Jolly","ForeName":"Angad","Initials":"A","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Dawood","ForeName":"Moez","Initials":"M","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Du","ForeName":"Haowei","Initials":"H","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Grochowski","ForeName":"Christopher M","Initials":"CM","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Jones","ForeName":"Edward G","Initials":"EG","AffiliationInfo":[{"Affiliation":"Division of Cardiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Jhangiani","ForeName":"Shalini N","Initials":"SN","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Wehrens","ForeName":"Xander H T","Initials":"XHT","AffiliationInfo":[{"Affiliation":"Division of Cardiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Liu","ForeName":"Pengfei","Initials":"P","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Baylor Genetics, Houston, TX, 77021, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Bi","ForeName":"Weimin","Initials":"W","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Baylor Genetics, Houston, TX, 77021, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Boerwinkle","ForeName":"Eric","Initials":"E","AffiliationInfo":[{"Affiliation":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Posey","ForeName":"Jennifer E","Initials":"JE","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Muzny","ForeName":"Donna M","Initials":"DM","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Gibbs","ForeName":"Richard A","Initials":"RA","AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Lupski","ForeName":"James R","Initials":"JR","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0001-9907-9246"}],"AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA."},{"Affiliation":"Texas Children's Hospital, Houston, Houston, TX, 77030, USA."},{"Affiliation":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Coban-Akdemir","ForeName":"Zeynep","Initials":"Z","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0001-9928-9032"}],"AffiliationInfo":[{"Affiliation":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. zeynep.h.cobanakdemir@uth.tmc.edu."},{"Affiliation":"Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. zeynep.h.cobanakdemir@uth.tmc.edu."}]},{"@attributes":{"ValidYN":"Y"},"LastName":"Morris","ForeName":"Shaine A","Initials":"SA","Identifier":[{"@attributes":{"Source":"ORCID"},"@text":"0000-0002-8056-0934"}],"AffiliationInfo":[{"Affiliation":"Division of Cardiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, 77030, USA. shainem@bcm.edu."}]}]},"Language":["eng"],"GrantList":{"@attributes":{"CompleteYN":"Y"},"Grant":[{"GrantID":"UM1 HG006542","Acronym":"HG","Agency":"NHGRI NIH HHS","Country":"United States"},{"GrantID":"R35 NS105078","Acronym":"NS","Agency":"NINDS NIH HHS","Country":"United States"},{"GrantID":"R01 HD039056","Acronym":"HD","Agency":"NICHD NIH HHS","Country":"United States"},{"GrantID":"R01 HL091771","Acronym":"HL","Agency":"NHLBI NIH HHS","Country":"United States"},{"GrantID":"U01 HG011758","Acronym":"HG","Agency":"NHGRI NIH HHS","Country":"United States"}]},"PublicationTypeList":{"PublicationType":[{"@attributes":{"UI":"D016428"},"@text":"Journal Article"},{"@attributes":{"UI":"D013485"},"@text":"Research Support, Non-U.S. Gov't"},{"@attributes":{"UI":"D052061"},"@text":"Research Support, N.I.H., Extramural"}]},"ArticleDate":[{"@attributes":{"DateType":"Electronic"},"Year":"2024","Month":"04","Day":"03"}]},"MedlineJournalInfo":{"Country":"England","MedlineTA":"Genome Med","NlmUniqueID":"101475844","ISSNLinking":"1756-994X"},"ChemicalList":{"Chemical":[{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"C526007"},"@text":"NODAL protein, human"}},{"RegistryNumber":"0","NameOfSubstance":{"@attributes":{"UI":"D055457"},"@text":"Nodal Protein"}}]},"CitationSubset":["IM"],"MeshHeadingList":{"MeshHeading":[{"DescriptorName":{"@attributes":{"UI":"D000818","MajorTopicYN":"N"},"@text":"Animals"}},{"DescriptorName":{"@attributes":{"UI":"D006801","MajorTopicYN":"N"},"@text":"Humans"}},{"DescriptorName":{"@attributes":{"UI":"D001158","MajorTopicYN":"N"},"@text":"Arteries"}},{"DescriptorName":{"@attributes":{"UI":"D055028","MajorTopicYN":"N"},"@text":"Comparative Genomic Hybridization"}},{"DescriptorName":{"@attributes":{"UI":"D006330","MajorTopicYN":"Y"},"@text":"Heart Defects, Congenital"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D059446","MajorTopicYN":"Y"},"@text":"Heterotaxy Syndrome"},"QualifierName":[{"@attributes":{"UI":"Q000235","MajorTopicYN":"N"},"@text":"genetics"}]},{"DescriptorName":{"@attributes":{"UI":"D010641","MajorTopicYN":"N"},"@text":"Phenotype"}},{"DescriptorName":{"@attributes":{"UI":"D014188","MajorTopicYN":"Y"},"@text":"Transposition of Great Vessels"}},{"DescriptorName":{"@attributes":{"UI":"D055457","MajorTopicYN":"N","AutoHM":"Y"},"@text":"Nodal Protein"}}]},"KeywordList":[{"@attributes":{"Owner":"NOTNLM"},"Keyword":[{"@attributes":{"MajorTopicYN":"N"},"@text":"NODAL"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Congenital heart disease"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Genetic diagnosis"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Heterotaxy"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Laterality defects"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Single ventricle"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Structural variation"},{"@attributes":{"MajorTopicYN":"N"},"@text":"Transposition"}]}],"CoiStatement":"J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple U.S. and European patents related to molecular diagnostics for inherited neuropathies, genomic disorders, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical genomic sequencing (both ES and WGS) offered in the Baylor Genetics Laboratory (http:\/\/bmgl.com). J.R.L. serves on the Scientific Advisory Board of BG. The remaining authors declare that they have no competing interests."},"PubmedData":{"History":{"PubMedPubDate":[{"@attributes":{"PubStatus":"received"},"Year":"2023","Month":"6","Day":"26"},{"@attributes":{"PubStatus":"accepted"},"Year":"2024","Month":"3","Day":"12"},{"@attributes":{"PubStatus":"medline"},"Year":"2024","Month":"4","Day":"5","Hour":"6","Minute":"44"},{"@attributes":{"PubStatus":"pubmed"},"Year":"2024","Month":"4","Day":"4","Hour":"0","Minute":"43"},{"@attributes":{"PubStatus":"entrez"},"Year":"2024","Month":"4","Day":"3","Hour":"23","Minute":"51"},{"@attributes":{"PubStatus":"pmc-release"},"Year":"2024","Month":"4","Day":"3"}]},"PublicationStatus":"epublish","ArticleIdList":{"ArticleId":[{"@attributes":{"IdType":"pubmed"},"@text":"38570875"},{"@attributes":{"IdType":"pmc"},"@text":"PMC10988827"},{"@attributes":{"IdType":"doi"},"@text":"10.1186\/s13073-024-01312-9"},{"@attributes":{"IdType":"pii"},"@text":"10.1186\/s13073-024-01312-9"}]},"ReferenceList":[{"Reference":[{"Citation":"Moran R, Robin NH. 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