Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease of the sarcomere. To date, four sacrcomeric loci have demonstrated significant genetic linkage to familial hypertrophic cardiomyopathy. These loci include the B-cardiac myosin heavy chain Tropmyosin-T, (-Troponin and myosin heavy chain binding gene located on chromosome 14, 1, 15 and 11 respectively. The mutations within these sarcomeric genes leading to familial hypertrophic cardiomyopathy are diverse and to date appear to be unique to a small number of families. The mutations occur at evolutionary conserved sequences within these proteins and perterb sites that interact with other components of the sacromere. This implies that hypertrophic cardiomyopathy is a disease of sarcomeric interaction. Our clinical observation demonstrates that there is great disparity in the phenotypic expression of hypertrophic cardiomyopathy within any one specific pedigree. This is despite each individual inheriting the same identical mutation in the pedigree. These observations coincide with published reports demonstrating variation of clinical expression, course and outcome within the same family or unrelated families with an identical point mutation. This suggests that the role of additional genetic factors that modulate the expression of hypertrophic cardiomyopathy. Similar modifiers have been demonstrated in other genetic disorders to explain phenotypic variations. To better understand the genetic basis of hypertrophic cardiomyopathy, we propose to identify genetic modifiers associated with specific phenotypes. We hypothesize that the expression of the primary mutation in familial hypertrophic cardiomyopathy can be modified by the genetic background of other scaromeric components. To this end we propose the following aims. Identify the etiology of familial hypertrophic cardiomyopathy in all families including those families that do not demonstrate significant genetic linkage to previously described HCM loci. Molecular characterization of mutations of candidate genes and other FHMC loci that demonstrates linkage to hypertrophic cardiomyopathy. Localize and identify genetic modifiers for hypertrophic cardiomyopathy. Study population will consist of any family with a history of familial hypertrophic cardiomyopathy. There must be at least 20-25 direct decendants in the family willing to participate in the study. This is because the power of linkage analysis is limited by this population size. If fewer than the required number are obtained, the family will be excluded from the study. Statistical analysis will be performed by genetic linkage analysis. The sample sizes have been deduced from pedigree simulation studies. Individuals will undergo a 2D echocardiogram to identify the presence or absence of phenotypic expression of hypertrophic cardiomyopathy. Blood will be collected from each individual. Lymphocytes will be isolated from the blood and genomic DNA purified. This DNA will be used for genetic analysis. Linkage analysis will be utilized to test candidate genes (sacromeric genes) for linkage to hypertrophic cardiomyopathy. When linkage is identified, a molecular analysis of the particular gene will be undertaken to identify the specific mutation. Once the specific mutation is identified then all individuals within the pedigree can be tested for the genetic predisposition to develop hypertrophic cardiomyopathy. The group of the affected individuals will then be stratified into two clinical groups; mildly or moderately affected. These individuals will then be genotyped to 25 other different sarcomeric proteins. Linkage analysis (segregation analysis) will then be undertaken to test whether a particular sarcomeric genotype segregates with a particular disease phenotype.
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