National Heart, Lung, and Blood Institute (NHLBI) Bench to Bassinet Program: The Pediatric Cardiac Genetics Consortium (PCGC)
Ontology highlight
ABSTRACT: Multi-center, prospective observational cohort study of individuals with congenital heart defects (CHD). Phenotypic data and source DNA of probands, parents, and families of interest are being collected to investigate relationships between genetic factors and phenotypic and clinical outcomes in patients with CHD.
PROVIDER: phs000571.v1.p1 | EGA |
REPOSITORIES: EGA
Publications
De novo mutations in histone-modifying genes in congenital heart disease.
Zaidi Samir S Choi Murim M Wakimoto Hiroko H Ma Lijiang L Jiang Jianming J Overton John D JD Romano-Adesman Angela A Bjornson Robert D RD Breitbart Roger E RE Brown Kerry K KK Carriero Nicholas J NJ Cheung Yee Him YH Deanfield John J DePalma Steve S Fakhro Khalid A KA Glessner Joseph J Hakonarson Hakon H Italia Michael J MJ Kaltman Jonathan R JR Kaski Juan J Kim Richard R Kline Jennie K JK Lee Teresa T Leipzig Jeremy J Lopez Alexander A Mane Shrikant M SM Mitchell Laura E LE Newburger Jane W JW Parfenov Michael M Pe'er Itsik I Porter George G Roberts Amy E AE Sachidanandam Ravi R Sanders Stephan J SJ Seiden Howard S HS State Mathew W MW Subramanian Sailakshmi S Tikhonova Irina R IR Wang Wei W Warburton Dorothy D White Peter S PS Williams Ismee A IA Zhao Hongyu H Seidman Jonathan G JG Brueckner Martina M Chung Wendy K WK Gelb Bruce D BD Goldmuntz Elizabeth E Seidman Christine E CE Lifton Richard P RP
Nature 20130512 7453
Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for da ...[more]
Similar Datasets
Project description:<p>The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource).</p> <p>Multi-center, prospective observational cohort study of individuals with congenital heart defects (CHD). Phenotypic data and source DNA derived from 300 probands and their parents, and family of interest collected to investigate relationships between genetic factors and phenotypic and clinical outcomes in patients with CHD.</p> <p>This Kids First project represents a subset of the PCGC data. Other PCGC data can be accessed through <a href="study.cgi?study_id=phs001194">phs001194</a> and other Kids First data can be accessed through <a href="https://kidsfirstdrc.org/" target="_blank">kidsfirstdrc.org</a>.</p>
| phs001138 | dbGaP
Project description:<p>Multi-center, prospective observational cohort study of individuals with congenital heart defects (CHD). Phenotypic data and source DNA derived from 10,000 probands, parents, and families of interest are being collected to investigate relationships between genetic factors and phenotypic and clinical outcomes in patients with CHD.</p> <p>The PCGC Cohort is utilized in the following dbGaP substudies. To view genotypes, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs001194 PCGC Cohort. <ul> <li><a href="./study.cgi?study_id=phs000571">phs000571</a> The Pediatric Cardiac Genetics Consortium (PCGC)</li> </ul> </p> <p>The Gabriella Miller Kids First Pediatric Research Program (Kids First) subset of the PCGC project (phs001194) is now accessible through a separate dbGaP study accession: <a href="./study.cgi?study_id=phs001138">phs001138</a>. To access this dataset, please submit a Data Access Request (DAR) for phs001138. Approval of this DAR will be expedited for approved users of phs001194. To learn about other Kids First datasets visit <a href="https://kidsfirstdrc.org/" target="_blank">https://kidsfirstdrc.org/</a>.</p>
| phs001194 | dbGaP
Project description:The goal of this study was to explore the miRNome profile in three frequently occurring Congenital Heart Disease (CHD) types, namely Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD) and Tetralogy of Fallot (TOF). For this purpose, we extracted total RNA from the cardiac tissues of patients with CHD and non-CHD, which was subjected to high-throughput sequencing technology to profile the miRNAs. The small RNA sequencing data was analyzed using the nf-core bioinformatic analysis pipeline. There were 40 up-regulated and 8 down-regulated miRNAs identified to be differentially expressed. These miRNAs are predicted to target several genes involved in regulatory pathways such as cell proliferation, differentiation, cell survival, etc. The results from this study are expected to expand the existing knowledge on molecular basis of CHD. Functional validation can throw insights on molecular epidemiology and therapy for heart diseases.
2022-10-02 | GSE185565 | GEO
Project description:Dysplasia of cardiac endothelial cells significantly contributes to congenital heart disease (CHD), the most common congenital disability. The regulatory role of miRNAs in this process remains elusive. This study identified elevated miR-187 expression in embryonic heart endothelial cells from CHD fetuses. Using a conditional knock-in model, we showed that increased miR-187 levels in embryonic endothelial cells induce CHD in homozygous fetal mice, closely mirroring human CHD. Mechanistically, miR-187 targets NIPBL, which is responsible for recruiting the cohesin complex and facilitating chromatin accessibility between enhancers and promoters. Consequently, the endothelial cell-specific upregulation of miR-187 inhibited NIPBL, leading to reduced chromatin accessibility and impaired gene expression, which hindered endothelial cell development and ultimately caused heart septal defects and reduced heart size both in vitro and in vivo. Importantly, exogenous miR-187 expression in human cardiac organoids mimicked developmental defects in the cardiac endothelial cells, reversible by NIPBL replenishment. Our findings establish the miR-187/NIPBL axis as a potent regulator that inhibits cardiac endothelial cell development by attenuating the transcription of numerous endothelial genes, with our mouse and human cardiac organoid models effectively replicating severe defects from minor perturbations.
2024-11-03 | GSE276222 | GEO
Project description:Dysplasia of cardiac endothelial cells significantly contributes to congenital heart disease (CHD), the most common congenital disability. The regulatory role of miRNAs in this process remains elusive. This study identified elevated miR-187 expression in embryonic heart endothelial cells from CHD fetuses. Using a conditional knock-in model, we showed that increased miR-187 levels in embryonic endothelial cells induce CHD in homozygous fetal mice, closely mirroring human CHD. Mechanistically, miR-187 targets NIPBL, which is responsible for recruiting the cohesin complex and facilitating chromatin accessibility between enhancers and promoters. Consequently, the endothelial cell-specific upregulation of miR-187 inhibited NIPBL, leading to reduced chromatin accessibility and impaired gene expression, which hindered endothelial cell development and ultimately caused heart septal defects and reduced heart size both in vitro and in vivo. Importantly, exogenous miR-187 expression in human cardiac organoids mimicked developmental defects in the cardiac endothelial cells, reversible by NIPBL replenishment. Our findings establish the miR-187/NIPBL axis as a potent regulator that inhibits cardiac endothelial cell development by attenuating the transcription of numerous endothelial genes, with our mouse and human cardiac organoid models effectively replicating severe defects from minor perturbations.
2024-11-03 | GSE275950 | GEO
Project description:About 45% of congenital heart disease (CHD) is caused by rare gene mutations. Non-coding mutations that perturb cis-regulatory elements (CREs) likely contribute to CHD among the remaining cases without clear etiology. However, identifying CHD-causing non-coding variants has been problematic. We combined human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) differentiation and a lentivirus-mediated massively parallel reporter assay (lentiMPRA) to create a high-throughput platform to measure human cardiac enhancer activity. We tested 2451 candidate human cardiac enhancers, identified 1185 with measurable activity, and functionally dissected 123 of these by systematic tiling mutagenesis. We functionally evaluated 6761 non-coding de novo variants (ncDNVs) prioritized from the whole genome sequencing (WGS) of 749 CHD trios. 397 ncDNVs significantly affected cardiac CRE activity. Remarkably, 53% of these ncDNVs increased enhancer activity, often at regions with undetectable enhancer activity in the reference sequence. We introduced 10 of these DNVs associated with CHD genes into iPSCs and found that 4 altered expression of neighboring genes. Moreover, these 4 DNVs also altered cardiomyocyte differentiation, as assessed by single nucleus RNA sequencing. Using the MPRA data, we developed a regression model to prioritize future DNVs for functional testing and demonstrate that this model finds enrichment of DNVs in a second, independent WGS cohort. Taken together, we developed a scalable system to measure the impact of non-coding DNVs on CRE activity and deployed this platform to systematically assess the contribution of non-coding DNVs to CHD.
2022-08-05 | GSE210376 | GEO
Project description:Congenital heart disease (CHD) is the most frequent birth defect and affects nearly 1% of newborns. The etiology of CHD is largely unknown and only a small percentage can be assigned to environmental risk factors such as maternal diseases or exposure to mutagenic agents during pregnancy. Chromosomal imbalances have been identified in many forms of syndromic CHD, but next to nothing is known about the impact of DNA copy number changes in non-syndromic CHD. Here we present a sub-megabase resolution array CGH screen of a cohort with CHD as the sole abnormality at the time of diagnosis. Keywords: array CGH In this BAC array CGH study 104 patients with congenital heart disease and some of their parents were screened for DNA copy number changes at submegabase resolution. No dye swap was performed.
2008-05-11 | E-GEOD-7527 | biostudies-arrayexpress
Project description:Dysplasia of cardiac endothelial cells significantly contributes to congenital heart disease (CHD), the most common congenital disability. The regulatory role of miRNAs in this process remains elusive. This study identified elevated miR-187 expression in embryonic heart endothelial cells from CHD fetuses. Using a conditional knock-in model, we showed that increased miR-187 levels in embryonic endothelial cells induce CHD in homozygous fetal mice, closely mirroring human CHD. Mechanistically, miR-187 targets NIPBL, which is responsible for recruiting the cohesin complex and facilitating chromatin accessibility between enhancers and promoters. Consequently, the endothelial cell-specific upregulation of miR-187 inhibited NIPBL, leading to reduced chromatin accessibility and impaired gene expression, which hindered endothelial cell development and ultimately caused heart septal defects and reduced heart size both in vitro and in vivo. Importantly, exogenous miR-187 expression in human cardiac organoids mimicked developmental defects in the cardiac endothelial cells, reversible by NIPBL replenishment. Our findings establish the miR-187/NIPBL axis as a potent regulator that inhibits cardiac endothelial cell development by attenuating the transcription of numerous endothelial genes, with our mouse and human cardiac organoid models effectively replicating severe defects from minor perturbations.
2024-11-03 | GSE275951 | GEO
Project description: Not available
| S-EPMC4905598 | biostudies-literature
Project description:Congenital heart disease (CHD) is the most prevalent structural malformations of the heart affecting ∼1% of live births. To date, both damaging genetic variations and adverse environmental exposure such as maternal diabetes have been found to cause CHD. Clinical studies show ∼fivefold higher risk of CHD in the offspring of mothers with pregestational diabetes. Maternal pregestational diabetes affects the gene regulatory networks key to proper cardiac development in the fetus. However, the cell-type specificity of these gene regulatory responses to maternal diabetes and their association with the observed cardiac defects in the fetuses remains unknown. To uncover the transcriptional responses to maternal diabetes in the early embryonic heart, we used an established murine model of pregestational diabetes. In this model, we have previously demonstrated an increased incidence of CHD. Here, we show maternal hyperglycemia (matHG) elicits diverse cellular responses during heart development by single-cell RNA-sequencing in embryonic hearts exposed to control and matHG environment. Through differential gene-expression and pseudotime trajectory analyses of this data, we identified changes in lineage specifying transcription factors, predominantly affecting Isl1+ second heart field progenitors and Tnnt2+cardiomyocytes with matHG. Using in vivo cell-lineage tracing studies, we confirmed that matHG exposure leads to impaired second heart field-derived cardiomyocyte differentiation. Finally, this work identifies matHG-mediated transcriptional determinants in cardiac cell lineages elevate CHD risk and show perturbations in Isl1-dependent gene-regulatory network (Isl1-GRN) affect cardiomyocyte differentiation. Functional analysis of this GRN in cardiac progenitor cells will provide further mechanistic insights into matHG-induced severity of CHD associated with diabetic pregnancies.
2022-07-22 | GSE193746 | GEO