NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy.

TitleNODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy.
Publication TypeJournal Article
Year of Publication2024
AuthorsDardas, Z, Fatih, JM, Jolly, A, Dawood, M, Du, H, Grochowski, CM, Jones, EG, Jhangiani, SN, Wehrens, XHT, Liu, P, Bi, W, Boerwinkle, E, Posey, JE, Muzny, DM, Gibbs, RA, Lupski, JR, Coban-Akdemir, Z, Morris, SA
JournalGenome Med
Date Published2024 Apr 03
KeywordsAnimals, Arteries, Comparative Genomic Hybridization, Heart Defects, Congenital, Heterotaxy Syndrome, Humans, Phenotype, Transposition of Great Vessels

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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 > A: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.

CONCLUSION: 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.

Alternate JournalGenome Med
PubMed ID38570875
PubMed Central IDPMC10988827
Grant ListR01 HL091771 / HL / NHLBI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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