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Molecular genetics of familial hypertrophic cardiomyopathy (FHC)
Murali D Bashyam1, Gorinabele R Savithri, Murugapiran S Kumar
1Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nacharam, Hyderabad 500076, India. bashyam@www.cdfd.org.in
Insights
Familial hypertrophic cardiomyopathy, a genetic heart disease, causes thickening of the heart muscle and is a leading cause of sudden cardiac death. Research is exploring its genetic basis and varied clinical presentations.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited cardiac condition.
- It is the most frequent cause of sudden cardiac death in young, healthy individuals.
- Key features include left ventricular hypertrophy and myocyte disarray, leading to symptoms like breathlessness, angina, and potentially sudden death.
Purpose of the Study:
- To review the current understanding of the molecular genetics of familial hypertrophic cardiomyopathy.
- To discuss the genetic heterogeneity and identified mutations in sarcomere protein genes.
- To explore the challenges in establishing genotype-phenotype correlations and the influence of non-genetic factors.
Main Methods:
- Review of current literature on familial hypertrophic cardiomyopathy genetics.
- Analysis of identified mutations in nine genes encoding sarcomere proteins.
- Discussion of genotype-phenotype correlation studies and modulating factors.
Main Results:
- Over 100 mutations in nine sarcomere protein genes have been identified as the molecular basis for HCM.
- Clinical heterogeneity of HCM is linked to genetic heterogeneity.
- Establishing precise genotype-phenotype correlations remains challenging, with non-genetic factors also influencing disease presentation.
Conclusions:
- Significant progress has been made in understanding the molecular genetics of familial hypertrophic cardiomyopathy.
- The complex interplay between genetic mutations, additional genetic loci, and non-genetic factors contributes to the diverse clinical manifestations of HCM.
- Further research is needed to elucidate how specific mutations lead to cardiac hypertrophy and myofibrillar disarray.
Abstract:
Familial hypertrophic cardiomyopathy is an autosomal dominant disease with a wide range of clinical features from benign to severe, and is the most common cause of sudden death in otherwise healthy individuals. The two prominent clinical features are left ventricular hypertrophy and myocyte/myofibrillar disarray. The former is responsible for clinical symptoms such as breathlessness and angina, whereas the latter may lead to sudden cardiac death. The last decade has seen an enormous improvement in our understanding of the molecular genetics of this disorder. The clinical heterogeneity has been linked to genetic heterogeneity; mutations in nine genes encoding sarcomere proteins have been shown to be the molecular basis for the disorder. However, attempts to establish a genotype-phenotype correlation for each of the more than 100 mutations that have been identified have not been highly successful. Additional genetic loci, as well as nongenetic factors such as lifestyle, sex, and age, have also been shown to play a role in modulating the clinical presentation of the disease. How each mutation results in hypertrophy and/or myofibrillar disarray is unclear. The present review discusses the current status of the molecular genetic characterization of this important disorder.
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