Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA275738 | ENA |
REPOSITORIES: ENA
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Project description:Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations that result in a heart unable to sustain systemic circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects (CHDs) has been mounting. However, the functional effects of such CNVs have not been examined, particularly in cases where the variant of interest is found in only a single patient. Initially whole-genome SNP microarrays were employed to detect CNVs in two patient cohorts (N = 70 total) predominantly diagnosed with some form of nonsyndromic HLHS. We discovered 16 rare variants adjacent to or overlapping 20 genes associated with cardiovascular or premature lethality phenotypes in mouse knockout models. Fifteen of the 16 variants were identified in separate patients, suggestive of a private mutation model of disease. We evaluated the impact of selected variants on the expression of nine of these genes through quantitative PCR on cDNA derived from patient heart tissue. Four genes displayed significantly altered expression in patients with an overlapping or proximal CNV verses patients without such CNVs. Thus, rare and private genomic imbalances perturb transcription of genes affecting cardiogenesis in a subset of nonsyndromic HLHS patients. Some of these genes influence extracellular matrix structure, cardiac neural crest development, and coronary vascularization. A total of 70 samples from CHD patients, mostly with nonsyndromic HLHS, yielded SNP genotypes and probe intensity ratios of sufficient quality for CNV identification. Two classes of CNV detection algorithms (HMM and CBS) were employed. After identification, concordant entries were subjected to selection criteria based on rarity and gene content, which produced putative candidate genes for follow-up experiments.
2015-12-10 | E-GEOD-66032 | biostudies-arrayexpress
Project description:Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations that result in a heart unable to sustain systemic circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects (CHDs) has been mounting. However, the functional effects of such CNVs have not been examined, particularly in cases where the variant of interest is found in only a single patient. Initially whole-genome SNP microarrays were employed to detect CNVs in two patient cohorts (N = 70 total) predominantly diagnosed with some form of nonsyndromic HLHS. We discovered 16 rare variants adjacent to or overlapping 20 genes associated with cardiovascular or premature lethality phenotypes in mouse knockout models. Fifteen of the 16 variants were identified in separate patients, suggestive of a private mutation model of disease. We evaluated the impact of selected variants on the expression of nine of these genes through quantitative PCR on cDNA derived from patient heart tissue. Four genes displayed significantly altered expression in patients with an overlapping or proximal CNV verses patients without such CNVs. Thus, rare and private genomic imbalances perturb transcription of genes affecting cardiogenesis in a subset of nonsyndromic HLHS patients. Some of these genes influence extracellular matrix structure, cardiac neural crest development, and coronary vascularization.
2015-12-10 | GSE66032 | GEO
Project description:This project aims to study exomes from families and trios with
congenital heart disease (CHD). The samples have been collected under
the Competence Network - Congenital Heart Defects in Berlin, Germany.
The phenotypes are mainly left ventricular outflow obstruction (aortic
stenosis, bicuspd aortic valve disease coarctation and hypoplastic
left heart), but will also include samples with hypoplastic right
heart and atrioventricular septal defects. We will perform whole exome
sequencing using Agilent sequence capture and Illumina HiSeq
sequencing.
| EGAS00001000368 | EGA
Project description:This project aims to study exomes from families and trios with
congenital heart disease (CHD). The samples have been collected under
the Competence Network - Congenital Heart Defects in Berlin, Germany.
The phenotypes are mainly left ventricular outflow obstruction (aortic
stenosis, bicuspd aortic valve disease coarctation and hypoplastic
left heart), but will also include samples with hypoplastic right
heart and atrioventricular septal defects. We will perform whole exome
sequencing using Agilent sequence capture and Illumina HiSeq
sequencing.
| EGAD00001000800 | EGA
Project description:Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects
| PRJNA359353 | ENA
Project description:Pathological variants in NOTCH1 have been implicated in multiple types of congenital heart defects including bicuspid aortic valve and hypoplastic left heart syndrome (HLHS). To probe how NOTCH1 deficiency affects cardiac development, we generated homozygous NOTCH1 knockout (N1KO) human induced pluripotent stem cells (iPSCs). We then ran single-cell RNA-seq to temporally profile transcriptomic changes during cardiac differentiation in wild type (WT) and N1KO iPSCs. We collected differentiating cells at multiple time points corresponding to different development stages, i.e., Day 0 (D0: pluripotent stem cell), D2 (mesoderm), D5 (cardiac mesoderm), D10 (cardiac progenitor), D14 (early cardiomyocyte), and D30 (fetal cardiomyocyte). Single-cell transcriptomics analysis reveals that NOTCH1 disruption impairs human ventricular cardiomyocyte differentiation and proliferation through balancing cell fate determination of cardiac mesoderm toward the first heart field, second heart field, and epicardial lineages.
2022-12-21 | GSE196632 | GEO
Project description:Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most severe congenital heart defect encompassing a spectrum of left-ventricular hypoplasia occurring in association with outflow-tract obstruction. The current clinical paradigm assumes HLHS is largely of hemodynamic origin. Here, by combining whole-exome sequencing of 87 HLHS parent-offspring trios and transcriptome of cardiomycytes (CMs) from healthy and patient native ventricles at different stages of development we identified perturbations in coherent gene programs controlling ventricular muscle lineage development. Single-cell and 3D molecular/functional modeling with iPSCs demonstrated intrinsic defects in the cell-cycle/ciliogenesis/autophagy hub resulting in disrupted differentiation of early cardiac progenitor (CP) lineages and ultimate defective CM-subtype differentiation/maturation in HLHS. Moreover, premature cellcycle exit of ventricular CM prevents tissue response to cues of developmental growth leading to multinucleation/polyploidy, accumulation of DNA damage, exacerbated apoptosis, and eventually ventricle hypoplasia. Our results highlight how genetic heterogeneity in HLHS converges in perturbations of sequential cellular processes driving cardiogenesis and facilitate potential novel nodes for therapy beside surgical intervention.
2022-02-15 | PXD014812 | Pride
Project description:The Dp1Tyb mouse model for Down syndrome contains a duplication of 23Mb of mouse chromosome 16 (Mmu16) that is orthologous to human chromosome 21 (Hsa21). This region contains 145 coding genes, and thus these genes are present in 3 copies. Dp1Tyb mice display congenital heart defects, similar to the ones seen in people with Down syndrome. These defects include ventricular and atrio-ventricular septal defects and are seen at embryonic day 14.5 (E14.5) of gestation. One of the 145 genes present in 3 copies in Dp1Tyb mice codes for a kinase called DYRK1A. We found that by crossing Dp1Tyb mice with mice carrying a heterozygous Dyrk1a loss of function allele, thereby reducing the dosage of the Dyrk1a gene from 3 to 2 copies, we rescue the congenital heart defects. Thus 3 copies of Dyrk1a are required to cause heart defects, and, presumably, increased DYRK1A protein is required for the heart defects. We compared the phosphoproteome in Dp1Tyb versus Dp1TybDyrk1a+/+/- embryonic hearts in order to discover alterations in phosphoproteins that could pinpoint molecular mechanisms that give rise to the congenital heart defects. The two strains (Dp1Tyb and Dp1TybDyrk1a+/+/-) differ only in the copy number of Dyrk1a (3 v 2) and thus differences in phosphoproteins would include both direct and indirect targets of DYRK1A activity.
2024-02-01 | PXD013053 | Pride
Project description:Hypoplastic left heart syndrome (HLHS) is one of the most devastating forms of congenital heart defects. Previous studies have only focused on intrinsic defects in the myocardium. However, this does not sufficiently explain the abnormal development of the cardiac valve, septum, and vasculature, which are known to originate from the endocardium. Here, using single-cell RNA profiling, induced pluripotent stem cells, and fetal heart tissue with an underdeveloped left ventricle, we identified a developmentally impaired endocardial cell population in HLHS. The intrinsic endocardial deficits contributed to abnormal endothelial to mesenchymal transition, NOTCH signaling, and extracellular matrix organization, all of which are key factors in valve formation. Consequentially, endocardial abnormalities conferred reduced proliferation and maturation of cardiomyocytes through a disrupted fibronectin-integrin interaction. Several known HLHS de novo mutations all contributed to the abnormal endocardial gene expression through the alteration of promoter/enhancer activities. These mechanistic discoveries provide an alternative angle for early intervention and heart regeneration in HLHS.
2020-08-17 | GSE138979 | GEO
Project description:Embryos from the Dp1Tyb mouse model for Down syndrome (DS) present with congenital heart defects similar to the heart defects seen in humans with DS. We found that genetically reducing the copy number of the Dyrk1a gene (one of the genes in 3 copies in DS) from 3 to 2, normalised some of the transcriptomic changes in Dp1Tyb embryonic hearts and rescued congenital heart defects. Here we treated pregnant mice carrying Dp1Tyb and wild-type (WT) embryos with a Dyrk1a pharmacological inhibitor (Leucettinib-21 or L21) or an inactive isomer (Iso-L21) to study the effect of L21 on the transcriptome of Dp1Tyb and WT embryonic hearts.
2024-01-25 | GSE239798 | GEO