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Single-Cell RNA-Seq and Patient-Specific iPSCs Reveal Endocardial Abnormalities in Hypoplastic Left Heart Syndrome

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138979 | GEO | 2020/08/17

REPOSITORIES: GEO

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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. Myocardial samples were isolated from the RV of 6 HLHS neonates, diagnosed based upon clinical features including hypoplasia/atresia of the ascending aorta, various degrees of underdevelopment of the aortic valve, mitral valve, and LV cavity, and retrograde flow in the aortic arch as determined by conventional 2-D echocardiography. The mean gestational age at birth of all subjects was 38 weeks (range 36-39) and the mean body weight at surgery of 2.7 kg (range 2.1-3.4 kg) (3 males, 3 females). All subjects were undergoing stage 1 Norwood reconstruction. Children with HLHS and other complex cardiac anomalies entailing non-HLHS single ventricle circulation were excluded from our study. For control samples, RV and LV myocardial tissue was obtained from 5 newborns aged between 1-28 days (mean 18 days; 3 males and 2 females) with normal cardiac anatomy and expired from non-cardiac diseases processes.

2011-12-31 | E-GEOD-23959 | biostudies-arrayexpress

Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome

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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

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2011-12-31 | GSE23959 | GEO

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Project description:Genetic Etiology of Hypoplastic Left Heart Syndrome (HLHS)

| PRJNA356955 | ENA

Impaired myocardial contractility underlies an Rbfox-mediated zebrafish model of hypoplastic left heart syndrome

Project description:Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, which was previously linked to HLHS in newborns, 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 contractility. On a molecular and cellular level, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 rescues ventricular structure and function in rbfox mutant zebrafish, demonstrating conservation of molecular function between humans and zebrafish Rbfox proteins. However, injection of RBFOX2 variants previously identified in newborns with HLHS do not. Taken together, our data suggest that mutations in RBFOX2 are causal for HLHS and challenge the obligate multigenic etiology of the disease. Instead, we provide a complimentary paradigm where HLHS can arise from a single gene mutation where ventricular, valve, and aortic deficiencies manifest secondary to a primary myocardial defect.

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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.

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