ArticleHuman genetics2015
Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome.
Article in Human genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions.Heart (British Cardiac Society) · 2022Pooled it
- Hypoplastic Left Heart Syndrome Cardiomyocytes Exhibit Intrinsic Stress Vulnerabilities and Augmented Stress Responses in vitro.Stem cell reviews and reports · 2026Article
- Is There a Unified Etiology of Hypoplastic Left Heart Syndrome? Evaluating Genetic, Structural, and Hemodynamic Models of Disease Initiation.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026Review
- Animal models of hypoplastic left heart syndrome: genetic and anatomical approaches.Pediatric research · 2026Review
- Article
- Review
- Notch signaling pathway and heart development, congenital heart disease, and myocardial regeneration.Frontiers in bioengineering and biotechnology · 2025Review
- Deciphering Congenital Heart Disease Using Human Induced Pluripotent Stem Cells.Advances in experimental medicine and biology · 2024Article
- Rare variants inHGG advances · 2023Article
- Charting the Path: Navigating Embryonic Development to Potentially Safeguard against Congenital Heart Defects.Journal of personalized medicine · 2023Review
- Article
- Unlocking the potential of induced pluripotent stem cells for neonatal disease modeling and drug development.Seminars in perinatology · 2023Review
- Use of Frogs as a Model to Study the Etiology of HLHS.Journal of cardiovascular development and disease · 2023Article
- Impaired Human Cardiac Cell Development due to NOTCH1 Deficiency.Circulation research · 2023Article
- Congenital aortic valve stenosis: from pathophysiology to molecular genetics and the need for novel therapeutics.Frontiers in cardiovascular medicine · 2023Review
- Transcriptome studies of congenital heart diseases: identifying current gaps and therapeutic frontiers.Frontiers in genetics · 2023Review
- Translational potential of hiPSCs in predictive modeling of heart development and disease.Birth defects research · 2022Review
- Probing single ventricle heart defects with patient-derived induced pluripotent stem cells and emerging technologies.Birth defects research · 2022Review
- ETS1 and HLHS: Implications for the Role of the Endocardium.Journal of cardiovascular development and disease · 2022Article
- Delving into the Molecular World of Single Ventricle Congenital Heart Disease.Current cardiology reports · 2022Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) that necessitates staged, single ventricle surgical palliation. An increased frequency of bicuspid aortic valve (BAV) has been observed among relatives. We postulated number of mutant alleles as a molecular basis for variable CHD expression in an extended family comprised of an HLHS proband and four family members who underwent echocardiography and whole-genome sequencing (WGS). Dermal fibroblast-derived induced pluripotent stem cells (iPSC) were procured from the proband-parent trio and bioengineered into cardiomyocytes. Cardiac phenotyping revealed aortic valve atresia and a slit-like left ventricular cavity in the HLHS proband, isolated bicuspid pulmonary valve in his mother, BAV in a maternal 4° relative, and no CHD in his father or sister. Filtering of WGS for rare, functional variants that segregated with CHD and were compound heterozygous in the HLHS proband identified NOTCH1 as the sole candidate gene. An unreported missense mutation (P1964L) in the cytoplasmic domain, segregating with semilunar valve malformation, was maternally inherited and a rare missense mutation (P1256L) in the extracellular domain, clinically silent in the heterozygous state, was paternally inherited. Patient-specific iPSCs exhibited diminished transcript levels of NOTCH1 signaling pathway components, impaired myocardiogenesis, and a higher prevalence of heterogeneous myofilament organization. Extended, phenotypically characterized families enable WGS-derived variant filtering for plausible Mendelian modes of inheritance, a powerful strategy to discover molecular underpinnings of CHD. Identification of compound heterozygous NOTCH1 mutations and iPSC-based functional modeling implicate mutant allele burden and impaired myogenic potential as mechanisms for HLHS.
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