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

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 trans...

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Autores principales: Matos-Nieves, Adrianna, Manivannan, Sathiyanarayanan, Majumdar, Uddalak, McBride, Kim L., White, Peter, Garg, Vidu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421733/
https://www.ncbi.nlm.nih.gov/pubmed/34504875
http://dx.doi.org/10.3389/fcvm.2021.683074
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author Matos-Nieves, Adrianna
Manivannan, Sathiyanarayanan
Majumdar, Uddalak
McBride, Kim L.
White, Peter
Garg, Vidu
author_facet Matos-Nieves, Adrianna
Manivannan, Sathiyanarayanan
Majumdar, Uddalak
McBride, Kim L.
White, Peter
Garg, Vidu
author_sort Matos-Nieves, Adrianna
collection PubMed
description 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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spelling pubmed-84217332021-09-08 A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes Matos-Nieves, Adrianna Manivannan, Sathiyanarayanan Majumdar, Uddalak McBride, Kim L. White, Peter Garg, Vidu Front Cardiovasc Med Cardiovascular Medicine 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. Frontiers Media S.A. 2021-08-24 /pmc/articles/PMC8421733/ /pubmed/34504875 http://dx.doi.org/10.3389/fcvm.2021.683074 Text en Copyright © 2021 Matos-Nieves, Manivannan, Majumdar, McBride, White and Garg. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Matos-Nieves, Adrianna
Manivannan, Sathiyanarayanan
Majumdar, Uddalak
McBride, Kim L.
White, Peter
Garg, Vidu
A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes
title A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes
title_full A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes
title_fullStr A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes
title_full_unstemmed A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes
title_short A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes
title_sort multi-omics approach using a mouse model of cardiac malformations for prioritization of human congenital heart disease contributing genes
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421733/
https://www.ncbi.nlm.nih.gov/pubmed/34504875
http://dx.doi.org/10.3389/fcvm.2021.683074
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