139 Identification of the major genetic contributors to tetralogy of fallot

Monaghan, Richard M.; Paige, D. J.; Keavney, Bernard

doi:10.1136/heartjnl-2019-bcs.136

Cited by 2 publications

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“…Comparison of the DEG-HH genes with a second cohort of TOF-patients was done using data set from Page et al (24). Page et al reported non-synonymous variants filtered using cutoffs in population frequency and CADD scores with damaging effects.…”

Section: Bioinformatics and Statistical Analysis For Human Chd Association Studiesmentioning

confidence: 99%

“…To determine the utility of our mouse to human comparative analysis pipeline, we performed a secondary analysis using a distinct cohort consisting of 829 non-syndromic TOF patients described by Page et al as described previously with minor modifications (Figure 5B; Supplementary Table 3D) (24). As the inheritance of these variants was not available, we generated a list of genes that were reported to possess at least one non-synonymous variant and also had a mouse homolog (TOF-VAR-PAGE-MH).…”

Section: Differentially Expressed Genes Inmentioning

confidence: 99%

“…A genome-wide chromosomal analysis of TOF patients identified de novo copy number variations in loci known to encode NOTCH1 and JAG1, a ligand for the NOTCH1 receptor, that were absent in controls further implicating genes in the Notch signaling pathway as potential contributors of disease (22). Exome sequencing methods in TOF patient populations identified disease-contributing variants in NOTCH1 and also allowed for the characterization of other genes such as FLT4, which encodes for VEGFR-3 (23)(24)(25). Meanwhile, an inspection of cardiac phenotypes in transgenic mouse models deficient in Fgf, Bmp, Slit/Robo, N-Cadherin, and Wnt signaling have also identified malformations of OFT structures with varying degrees of penetrance (6,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

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A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes

Matos‐Nieves

Manivannan

Majumdar

et al. 2021

Front. Cardiovasc. Med.

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Congenital heart disease (CHD) is the most common type of birth defect, affecting ~1% of all live births. Malformations of the cardiac outflow tract (OFT) account for ~30% of all CHD and include a range of CHDs from bicuspid aortic valve (BAV) to tetralogy of Fallot (TOF). We hypothesized that transcriptomic profiling of a mouse model of CHD would highlight disease-contributing genes implicated in congenital cardiac malformations in humans. To test this hypothesis, we utilized global transcriptional profiling differences from a mouse model of OFT malformations to prioritize damaging, de novo variants identified from exome sequencing datasets from published cohorts of CHD patients. Notch1+/−; Nos3−/− mice display a spectrum of cardiac OFT malformations ranging from BAV, semilunar valve (SLV) stenosis to TOF. Global transcriptional profiling of the E13.5 Notch1+/−; Nos3−/− mutant mouse OFTs and wildtype controls was performed by RNA sequencing (RNA-Seq). Analysis of the RNA-Seq dataset demonstrated genes belonging to the Hif1α, Tgf-β, Hippo, and Wnt signaling pathways were differentially expressed in the mutant OFT. Mouse to human comparative analysis was then performed to determine if patients with TOF and SLV stenosis display an increased burden of damaging, genetic variants in gene homologs that were dysregulated in Notch1+/−; Nos3−/− OFT. We found an enrichment of de novo variants in the TOF population among the 1,352 significantly differentially expressed genes in Notch1+/−; Nos3−/− mouse OFT but not the SLV population. This association was not significant when comparing only highly expressed genes in the murine OFT to de novo variants in the TOF population. These results suggest that transcriptomic datasets generated from the appropriate temporal, anatomic and cellular tissues from murine models of CHD may provide a novel approach for the prioritization of disease-contributing genes in patients with CHD.

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Section: Bioinformatics and Statistical Analysis For Human Chd Association Studiesmentioning

confidence: 99%

Section: Differentially Expressed Genes Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes

Matos‐Nieves

Manivannan

Majumdar

et al. 2021

Front. Cardiovasc. Med.

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Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

Wang

Xie

et al. 2022

Front. Cardiovasc. Med.

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BackgroundRare genetic variants have been identified to be important contributors to the risk of Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). But relatively limited familial studies with small numbers of TOF cases have been reported to date. In this study, we aimed to identify novel pathogenic genes and variants that caused TOF in a Chinese family using whole exome sequencing (WES).MethodsA Chinese family whose twins were affected by TOF were recruited for this study. A WES was performed for the affected twins, their healthy brother, and parents to identify the potential pathogenic mutated gene(s). Heterozygous variants carried by the twins, but not the unaffected brother, were retained. Public databases were used to assess the frequencies of the selected variants, and online prediction tools were accessed to predict the influences of these variants on protein function. The final candidate variant was further confirmed by Sanger sequencing in other members of the family.ResultsAfter several filtering processes, a heterozygous missense variant in the MYOM2 gene (NM_003970.4:c.3097C>T:p.R1033C) was identified and confirmed by Sanger sequencing in the affected twins and their unaffected father, suggesting an inheritance pattern with incomplete penetrance. The variant was found to be extremely rare in the public databases. Furthermore, the mutated site was highly conserved among mammals, and as shown using multiple online prediction tools, this variant was predicted to be a detrimental variant.ConclusionWe assessed a family with TOF caused by a rare heterozygous missense variant of MYOM2. Our findings not only further confirm the significant role of genetics in the incidence of TOF but also expand the spectrum of the gene variants that lead to TOF.

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139 Identification of the major genetic contributors to tetralogy of fallot

Cited by 2 publications

References 0 publications

A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes

A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes

Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

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