biostudies-literatureDardas ZNational Institute of Neurological Disorders and StrokeBaylor-Hopkins Center for Mendelian GenomicsFoundation for the National Institutes of HealthGenomic Research Elucidates the Genetics of Rare diseaseNINDS NIH HHS53https://www.ebi.ac.uk/biostudies/studies/S-EPMC10988827biostudies-literatureUnknown16(1)<h4>Background</h4>NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/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.<h4>Methods</h4>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 tGenome medicineNODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy.PMC10988827UM1HG006542UM1 HG0117585RO1 HL091771R35 NS1050785RO1 HD039056Bi WMorris SAWehrens XHTGrochowski CMMuzny DMJhangiani SNPosey JEJones EGLiu PGibbs RABoerwinkle EJolly ACoban-Akdemir ZFatih JMDardas ZDu HDawood MLupski JRfalseNODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy.<h4>Background</h4>NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/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.<h4>Methods</h4>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 t2024-01-01T00:00:00Z2024 Apr2025-05-18T10:40:27.417Z2025-05-18T10:40:27.417ZS-EPMC109888273857087510.1186/s13073-024-01312-9