Modifying Factors and Phenotype Heterogeneity in Familial Hypertrophic Cardiomyopathy

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Familial Hypertrophic Cardiomyopathy (FHC) is an inherited disorder characterised by abnormal thickening of heart muscle, resulting in clinical symptoms in affected individuals ranging from mild symptoms, to heart failure and sudden death. FHC is the commonest cause of sudden death in individuals aged less than 35 yrs in our community, and is caused by defects in genes (DNA) important in the heart's cellular structure and function. Understanding and identifying the molecular steps involved in how this defect in our DNA can lead to the clinical features of FHC, is the focus of the research described in this project. A common occurrence in families with FHC is the identification of two affected individuals within the same family (e.g. siblings) and who therefore have the same genetic defect, with variable clinical outcomes. For example, one sibling may have no symptoms and live a normal life, while his-her sibling, may develop severe symptoms, heart failure, and-or early sudden death. The reason for such diversity in clinical features, even amongst individuals with the same genetic defect, most likely reflects secondary modifying factors, e.g. genetic and-or environmental factors which modulate the expression of the primary FHC-causing gene defect. This project will focus on identifying and studying such modifying factors. One aspect of the project will focus on the identification of a genetic modifier which has been shown to exist in a genetically-engineered mouse model of FHC. A second aspect of the proposed research will focus on potential environmental factors, including pharmacological agents which may prevent disease progression, dietary factors, e.g. caffeine intake, and lifestyle factors , e.g. exercise. Through these studies, it is hoped that key molecules and important pathogenic mechanisms will be identified, leading to the development of potentially new therapies, to both treat, and ultimately prevent or cure this inherited cardiac disorder.