|
| Status |
Public on Jun 28, 2021 |
| Title |
A multi-omics approach using a mouse model of cardiac malformations for prioritization of human congenital heart disease contributing genes [scRNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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 compared to only highly expressed genes in the murine OFT and of 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.
|
| |
|
| Overall design |
E12.5 cardiac OFTs (both Notch1+/- and wildtype) were microdissected from five mouse embryos and pooled for single-cell RNA sequencing
|
| |
|
| Contributor(s) |
Manivannan S, Majumdar U, Matos-Nieves A, Garg V |
| Citation(s) |
34504875 |
| |
| Submission date |
Mar 31, 2021 |
| Last update date |
Sep 15, 2021 |
| Contact name |
Vidu Garg |
| E-mail(s) |
vidu.garg@nationwidechildrens.org
|
| Phone |
614-355-5710
|
| Organization name |
Research Institute at Nationwide Children's Hospital
|
| Department |
Cardiovascular Research
|
| Lab |
Vidu Garg
|
| Street address |
700 Children's Drive WB4239
|
| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43205 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
|
| Samples (1) |
|
| This SubSeries is part of SuperSeries: |
| GSE171239 |
A multi-omics approach using a mouse model of cardiac malformations for prioritization of human congenital heart disease contributing genes |
|
| Relations |
| BioProject |
PRJNA718840 |
| SRA |
SRP312903 |
