Genetic Etiology of Hypoplastic Left Heart Syndrome (HLHS)
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PROVIDER: PRJNA356955 | ENA |
REPOSITORIES: ENA
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Project description:Single cell transcriptome analysis was performed on one Hypoplastic Left Heart Synrome (HLHS) cell line and one control cell line.
2020-03-11 | GSE146763 | GEO
Project description:Congenital heart disease (CHD) is a prevalent birth defect affecting up to 1% of live births. While a genetic etiology is indicated by increased recurrence risk and association with chromosomal abnormalities, the genetics of CHD is poorly understood and likely complex. Here we show hypoplastic left heart syndrome (HLHS), a severe CHD with high morbidity/mortality, has a multigenic etiology. Analysis of 8 HLHS mutant mouse lines recovered from a large-scale mutagenesis screen showed no mutations are shared in common. In the *Ohia* mouse line, mutations in 2 genes, *Pcdha9*/*Sap130*, act synergistically to cause HLHS. Cardiomyocyte proliferation and differentiation defects likely act in concert with valve abnormalities to cause HLHS. Network analysis of mutations recovered in HLHS mice and 68 HLHS patients point to Notch signaling disruption, a pathway previously implicated in HLHS. These findings demonstrate large-scale mutagenesis is an effective systems approach for interrogating the complex genetics of human diseases. SUBMITTER_CITATION: Journal: Nature Genetics Title: The complex genetics of hypoplastic left heart syndrome Author names: Xiaoqin Liu1, Hisato Yagi1, Shazina Saeed1, Abha S. Bais1, George C. Gabriel1, Zhaohan Chen1, Kevin A. Peterson4, You Li1, Molly C. Schwartz1, William T. Reynolds1, Manush Saydmohammed1, Brian Gibbs1, Yijen Wu1, William Devine1, Bishwanath Chatterjee1, Nikolai T. Klena1, Dennis Kostka1, Karen L. de Mesy Bentley5, Madhavi K.Ganapathiraju2, Phillip Dexheimer11, Linda Leatherbury7, Omar Khalifa1, Anchit Bhagat1, Maliha Zahid1, William Pu8, Simon Watkins3, Paul Grossfeld9, Stephen Murray4, George A. Porter, Jr.6, Michael Tsang1, Lisa J.Martin10, D.Woodrow.Benson12, Bruce J. Aronow11, Cecilia W. Lo1
2017-04-13 | GSE77799 | GEO
Project description:Congenital heart disease (CHD) is a prevalent birth defect affecting up to 1% of live births. While a genetic etiology is indicated by increased recurrence risk and association with chromosomal abnormalities, the genetics of CHD is poorly understood and likely complex. Here we show hypoplastic left heart syndrome (HLHS), a severe CHD with high morbidity/mortality, has a multigenic etiology. Analysis of 8 HLHS mutant mouse lines recovered from a large-scale mutagenesis screen showed no mutations are shared in common. In the *Ohia* mouse line, mutations in 2 genes, *Pcdha9*/*Sap130*, act synergistically to cause HLHS. Cardiomyocyte proliferation and differentiation defects likely act in concert with valve abnormalities to cause HLHS. Network analysis of mutations recovered in HLHS mice and 68 HLHS patients point to Notch signaling disruption, a pathway previously implicated in HLHS. These findings demonstrate large-scale mutagenesis is an effective systems approach for interrogating the complex genetics of human diseases.
2017-04-13 | GSE77798 | GEO
Project description:Hypoplastic Left Heart Syndrome Single Cell RNA Sequencing
| PRJNA611831 | ENA
Project description:The complex genetics of hypoplastic left heart syndrome
| PRJNA311577 | ENA
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:Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta1. Although the mechanisms of disease pathogenesis remain elusive due to a paucity of candidate genes and animal models, prevailing paradigm suggests that HLHS is a multigenic disease of co-occurring phenotypes2,3. Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene previously linked to HLHS in humans4,5, display cardiovascular defects overlapping those in HLHS patients. In contrast to current models, we demonstrate that co-existing ventricular, valve, and aortic deficiencies in rbfox mutant zebrafish arise secondary to impaired myocardial function as all three phenotypes are rescued when Rbfox is expressed specifically in the myocardium. On a molecular and cellular level, we find diminished expression and alternative splicing of sarcomere and mitochondrial components in rbfox-deficient hearts that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 mRNA restores ventricular structure and function in rbfox mutant zebrafish, while HLHS-linked RBFOX2 variants fail to rescue. Taken together, our data suggest that mutations in RBFOX2 are causal for HLHS pathogenesis and provide a complimentary paradigm for HLHS emergence where co-existing ventricular, valve, and aortic deficiencies have a monogenic etiology caused by myocardial dysfunction.
2022-07-12 | MTBLS4176 | MetaboLights
Project description:<p>To understand the genetic etiology of hypoplastic left heart syndrome (HLHS), patients with HLHS were consented and recruited, with blood drawn for DNA extraction and exome sequencing. Using the exome sequencing dataset obtained, rare coding sequence variants were recovered and enrichment analysis was carried out to identify genes and pathways that are likely to contribute to HLHS. </p>
| phs001256 | dbGaP
Project description:Affymetrix GeneChip Exon-1.0ST was used to study the differential gene profiles in RV (right ventricle) samples from neonates with HLHS (hypoplastic left heart syndrome) versus RV and LV (left ventricle) samples obtained from age-matched controls. Although few significant changes were observed in the genetic profiles between control LV and control RV, many genes passed the false discovery rate in comparing HLHS-RV to RV and LV control groups, with greater differential profiles noted between HLHS-RV and control RV.
2011-12-31 | GSE23959 | GEO
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