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Updated: Oct 20, 2025
A Pipeline to Characterize Structural Heart Defects in the Fetal Mouse
Published on: December 16, 2022
A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart
Adrianna Matos-Nieves1, Sathiyanarayanan Manivannan1, Uddalak Majumdar1
1Center for Cardiovascular Research and Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.
Insights
Transcriptomic profiling of a mouse model for congenital heart disease (CHD) identified differentially expressed genes. This approach prioritized genetic variants in human patients with Tetralogy of Fallot (TOF), offering a new method for CHD gene discovery.
Area of Science:
- Developmental Biology
- Genetics
- Genomics
Background:
- Congenital heart disease (CHD) affects approximately 1% of live births, with outflow tract (OFT) malformations comprising about 30%.
- Identifying causative genes for CHD remains a challenge, necessitating novel approaches for genetic variant prioritization.
Purpose of the Study:
- To investigate the utility of transcriptomic profiling in a mouse model of OFT malformations for identifying disease-contributing genes in human CHD.
- To prioritize damaging, de novo variants in human CHD patient cohorts by comparing them with dysregulated genes in a mouse model.
Main Methods:
- Utilized a mouse model (Notch1+/-; Nos3-/-) exhibiting a spectrum of OFT malformations.
- Performed global transcriptional profiling via RNA sequencing (RNA-Seq) on mutant and wildtype mouse OFTs.
- Correlated differentially expressed genes with de novo variants in exome sequencing data from human CHD patient cohorts (TOF and Semilunar Valve stenosis).
Main Results:
- RNA-Seq analysis revealed differential expression of genes in key signaling pathways (Hif1α, Tgf-β, Hippo, Wnt) in the mutant OFT.
- An enrichment of de novo variants was observed in the Tetralogy of Fallot (TOF) patient population within the set of differentially expressed genes from the mouse model.
- This enrichment was not significant for Semilunar Valve (SLV) stenosis patients or when considering only highly expressed genes.
Conclusions:
- Transcriptomic data from appropriate murine models can effectively prioritize disease-contributing genes for human CHD.
- This approach shows promise for identifying genetic variants associated with Tetralogy of Fallot (TOF).
- Further research is warranted to refine this method for other CHD subtypes.
Abstract:
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.
