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.
Highlights
As the most common type of birth defect, congenital heart disease (CHD) affects nearly ∼1% of all live births [1]
We previously reported a spectrum of cardiac outflow tract (OFT) malformations including highly penetrant thickened, malformed semilunar valves and the partially penetrant phenotypes consisting of ventricular septal defects and an overriding aorta in Notch1+/−; Nos3−/− embryos [37, 38]
Using the Notch1+/−; Nos3−/− mouse as a genetic tool, we wanted to determine if genes differentially expressed in cells required for the development of the cardiac outflow tract are predictive of damaging de novo variants in patients with OFT malformations (Figure 1)
Summary
As the most common type of birth defect, congenital heart disease (CHD) affects nearly ∼1% of all live births [1]. Malformations of the cardiac outflow tract (OFT), which include incorrect positioning or septation of the major vessels (aorta and pulmonary artery) as well as anomalies of the aortic or pulmonic (semilunar) valves, account for an estimated 30% of CHD cases [1]. These types of malformations range from the simple to the more complex such as bicuspid aortic valve (BAV) and tetralogy of Fallot, respectively. Tetralogy of Fallot (TOF), is one of the more complex forms of CHD affecting the OFT in which abnormal positioning of the aorticopulmonary septum leads to pulmonic valve stenosis and a ventricular septal defect. Conotruncal heart defects compose a significant and growing portion of adult CHD survivors, but the genetic contributors for the majority of cases have not been defined
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