Hypertrophic cardiomyopathy (CMH) is characterized by unexplained cardiac hypertrophy: thickening of the myocardial wall in the absence of any other identifiable cause for left ventricular hypertrophy such as systemic hypertension or valvular heart disease. Myocyte hypertrophy, disarray, and fibrosis are the histopathologic hallmarks of this disorder. Clinical features are diverse and include arrhythmias, sudden cardiac death, and heart failure. With an estimated prevalence of 1 in 500, CMH is the most common cardiovascular genetic disease and the most common cause of sudden death in competitive athletes in the United States (summary by Song et al., 2006).

For a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600).

Song et al. (2006) studied 32 individuals from a large 4-generation family segregating autosomal dominant hypertrophic cardiomyopathy. The 9 affected family members had left ventricular hypertrophy (LVH) by electrocardiography (ECG) and/or echocardiography; the youngest patient was diagnosed at 13 years of age, at which time he was asymptomatic but had LVH and right axis deviation on ECG and mild LVH with mitral valve prolapse on echocardiography. Eight of the 9 patients had left ventricular end-diastolic diameters (LVEDD) of 5.1 cm or less and ejection fractions that were at least 60 to 65%. The remaining patient was a 61-year-old woman who underwent cardiac transplantation for heart failure at 49 years of age. She presented with what was initially thought to be dilated cardiomyopathy (CMD); the explanted heart showed marked cardiomegaly (1035 g) caused by chamber dilation, but histologic findings were nonspecific and nondiagnostic, without intramyocardial arteriolar medial hypertrophy or myocyte disarray. Another family member, who was reported to have had congenital subaortic membrane that was resected at 16 years of age, died suddenly at 40 years of age; serial echocardiograms in the years prior to his death were reported to show 'mild septal hypertrophy' and mild cavity enlargement to an LVEDD of 5.7 cm. Histopathologic examination showed mild interstitial fibrosis and myocyte hypertrophy but no disarray. Although this family member was designated as having an 'unknown' phenotype, persistent LVH and sudden death 24 years after treatment for subvalvular stenosis suggested the presence of a primary cardiomyopathy. No family members showed evidence of abnormal LV trabeculation or noncompaction.

In a large 4-generation family segregating autosomal dominant hypertrophic cardiomyopathy, in which mutation in the 8 sarcomere genes most commonly associated with CMH as well as the PRKAG2 gene (602743) had been ruled out, Song et al. (2006) performed genomewide linkage analysis and obtained a maximum lod score of 4.11 (theta = 0) at D7S669. Analysis of recombination events defined a 27.2-Mb critical disease interval on chromosome 7p12.1-q21.

Exclusion Studies

In a large 4-generation family segregating autosomal dominant hypertrophic cardiomyopathy mapping to chromosome 7p12.1-q21, Song et al. (2006) analyzed 9 candidate genes and did not identify any disease-causing mutations.