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Molecular and clinical aspects of inherited cardiomyopathies
J B Durand1, A B Abchee, R Roberts
1Baylor College of Medicine, Houston, Texas 77030, USA.
Insights
Genetic mutations in sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). Identifying these genetic defects aids in diagnosis, prognosis, and management of this heterogeneous heart disease.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous cardiac disease.
- Identified genetic loci for HCM include those encoding sarcomeric proteins like beta-myosin heavy chain (beta-MHC), cardiac troponin-T, and alpha-tropomyosin.
- These genetic variations suggest HCM is fundamentally a disease of the sarcomere.
Purpose of the Study:
- To review the genetic underpinnings of hypertrophic cardiomyopathy.
- To highlight the role of sarcomeric protein gene mutations in HCM pathogenesis.
- To discuss the diagnostic and prognostic implications of identified mutations.
Main Methods:
- Review of genetic studies identifying chromosomal loci and specific genes associated with HCM.
- Analysis of identified mutations within beta-MHC, cardiac troponin-T, and alpha-tropomyosin genes.
- Correlation of genetic findings with clinical phenotype and prognosis.
Main Results:
- Over 40 missense mutations and one deletion in the beta-MHC gene have been identified.
- Missense mutations in alpha-tropomyosin and cardiac troponin-T genes are also implicated in HCM.
- Genetic studies, including de novo mutations, confirm the causative role of these mutations in HCM.
- Molecular pathogenesis involves a compensatory response to primary sarcomeric defects.
Conclusions:
- Genetic mutations in sarcomeric proteins are definitively linked to hypertrophic cardiomyopathy.
- Identifying these mutations offers definitive presymptomatic diagnosis and holds significant predictive value for clinical prognosis.
- Genetic insights are crucial for effective genetic counseling and medical management of HCM patients.
Abstract:
Hypertrophic cardiomyopathy (HCM) is phenotypically and genotypically a heterogeneous disease. Since 1989, four chromosomal loci have been identified for HCM and the genes residing on three of these have been identified as beta-myosin heavy chain (beta-MHC), cardiac troponin-T and alpha-tropomyosin. These genes code for sarcomeric proteins and exhibit the same phenotype, suggesting that HCM is a disease of the sarcomere. Over 40 missense mutations and one deletion of the beta-MHC gene have been identified. Similarly, missense mutations in the alpha-tropomyosin gene and the cardiac troponin-T gene have been identified. From genetic studies, including de novo mutations, it is established that these mutations are indeed responsible for HCM. The molecular basis of the pathogenesis of the cardiac hypertrophy appears to be a compensatory response to the primary defect. In addition to providing a definitive presymptomatic diagnosis, studies correlating beta-MHC mutations with clinical prognosis suggest they have significant predictive value and can be helpful in genetic counselling and medical management. Dilated cardiomiopathies (DCM), the most common form of cardiomyopathies, have an estimated prevalence of nearly 40 per 100,000 individuals, and are the most common cause for cardiac transplantation in the United States. Familial dilated cardiomyopathy is thought to account for approximately 20% of the so-called cases of idiopathic DCM.