Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart
Jeanne L Theis1, Sybil C L Hrstka, Jared M Evans
1Cardiovascular Genetics Research Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
Insights
Genetic analysis of a family with hypoplastic left heart syndrome (HLHS) identified compound heterozygous NOTCH1 mutations. This suggests that the burden of mutant alleles and impaired heart muscle development contribute to HLHS.
Area of Science:
- Genetics
- Cardiology
- Developmental Biology
Background:
- Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) requiring complex surgical palliation.
- An increased incidence of bicuspid aortic valve (BAV) is noted in relatives of HLHS patients, suggesting a potential genetic link.
- Understanding the genetic basis of variable CHD expression is crucial for improved diagnosis and treatment.
Purpose of the Study:
- To investigate the molecular underpinnings of variable congenital heart defect (CHD) expression within an extended family affected by hypoplastic left heart syndrome (HLHS).
- To identify genetic variants associated with CHD by analyzing whole-genome sequencing (WGS) data from family members with varying cardiac phenotypes.
- To functionally model the impact of identified genetic mutations using patient-derived induced pluripotent stem cells (iPSCs).
Main Methods:
- Whole-genome sequencing (WGS) was performed on an extended family including an HLHS proband and relatives with diverse CHD phenotypes.
- Dermal fibroblast-derived induced pluripotent stem cells (iPSCs) were generated from the proband and parents and differentiated into cardiomyocytes.
- Cardiac phenotyping, WGS data filtering for rare, functional, and segregating variants, and iPSC-based functional assays were employed.
Main Results:
- Cardiac phenotyping revealed distinct CHD manifestations, including aortic valve atresia in the HLHS proband and bicuspid valves in relatives.
- Filtering of WGS data identified compound heterozygous NOTCH1 mutations as the sole candidate gene segregating with CHD.
- Patient-specific iPSCs exhibited reduced NOTCH1 signaling, impaired myocardiogenesis, and abnormal myofilament organization.
Conclusions:
- Compound heterozygous NOTCH1 mutations, inherited from both parents, are implicated in the pathogenesis of HLHS in this family.
- Mutant allele burden and impaired myogenic potential, as evidenced by iPSC modeling, are proposed mechanisms contributing to HLHS.
- This study highlights the power of WGS in extended families to uncover the genetic basis of complex CHD phenotypes.
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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