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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 <jats:italic>NODAL<\/jats:italic> variants in a large number of individuals with laterality defects.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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 <jats:italic>NODAL<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Missense, nonsense, splice site, indels, and\/or structural variants of <jats:italic>NODAL<\/jats:italic> 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 <jats:italic>NODAL<\/jats:italic> in two unrelated CHD cases. Furthermore, 17 CHD individuals were found (16\/17 with known Hispanic ancestry) to have the c.778G\u2009&gt;\u2009A:p.G260R <jats:italic>NODAL<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our data further support a role for rare deleterious variants in <jats:italic>NODAL<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13073-024-01312-9","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T11:02:08Z","timestamp":1712142128000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy"],"prefix":"10.1186","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2387-3122","authenticated-orcid":false,"given":"Zain","family":"Dardas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jawid M.","family":"Fatih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angad","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moez","family":"Dawood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haowei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Grochowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward G.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini N.","family":"Jhangiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xander H. 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Cited 2023 Apr 15.","journal-title":"HGG Adv"}],"container-title":["Genome Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-024-01312-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-024-01312-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-024-01312-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T18:07:29Z","timestamp":1724177249000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomemedicine.biomedcentral.com\/articles\/10.1186\/s13073-024-01312-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,3]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1312"],"URL":"https:\/\/doi.org\/10.1186\/s13073-024-01312-9","relation":{},"ISSN":["1756-994X"],"issn-type":[{"value":"1756-994X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,3]]},"assertion":[{"value":"26 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Institutional Review Board of Baylor College of Medicine approved all research study protocols. Written informed consent was obtained from all participating individuals including probands and any available family members from Group 1. For the clinically tested patients (Group 2), a waiver of consent was granted as part of 2 retrospective cohort studies of clinical genetic testing in CHD (IRB approval numbers: H-48014 and H-41191). These approvals were obtained in accordance with the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"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 (). J.R.L. serves on the Scientific Advisory Board of BG. The remaining authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"53"}}