Cardiomyopathy, Familial Hypertrophic, 11

A number sign (#) is used with this entry because familial hypertrophic cardiomyopathy-11 is caused by heterozygous mutation in the ACTC1 gene (102540) on chromosome 15q14.

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

Clinical Features

Olson et al. (2000) studied 2 sporadic patients with apical hypertrophic cardiomyopathy (CMH) and a 4-generation family segregating autosomal dominant CMH. The 2 sporadic patients had early-onset nonobstructive CMH involving the interventricular septum and left ventricular apex; left ventricular dimensions and shortening fractions were normal, demonstrating no features of dilated cardiomyopathy (CMD; see 613424). In the 4-generation kindred, the cardiomyopathy was later in onset and involved apical left ventricular hypertrophy in 5 cases and a trabeculated apex in 2 cases; 2 patients also had marked hypertrophy of the interventricular septum without outflow tract obstruction. Left ventricular dimensions were increased with normal shortening fractions in 2 patients; Olson et al. (2000) noted that in one of them, the dilation might have been a consequence of post-cardiac arrest myocardial injury and/or late-stage CMH, and in the other, a 25-year-old asymptomatic competitive athlete with a trabeculated apex and repaired atrial septal defect, the dilation might have been physiologic.

Arad et al. (2005) studied 18 mutation-positive members of 2 families segregating autosomal dominant apical CMH (see MOLECULAR GENETICS section) and found that 2 individuals, aged 10 and 29 years, had no clinical evidence of cardiomyopathy. Isolated apical hypertrophy was found in 5 individuals; 11 others also had mild thickening of the basal segments and/or involvement of the midventricular segment, and 2 also had trabeculation of the apex. Systolic ventricular function was preserved in all affected individuals; none had an outflow or midcavitary gradient, and 2 had significant mitral regurgitation. Right ventricular endomyocardial biopsy in a 43-year-old man who underwent cardiac catheterization due to increasing dyspnea revealed myocyte hypertrophy and disarray with extensive replacement fibrosis that was more marked than that typically seen in CMH associated with other morphologic patterns of hypertrophy. Electrocardiograms (ECGs) in affected family members showed voltage criteria for left ventricular hypertrophy (LVH) in only 2 individuals; T-wave inversion and ST-T segment abnormalities were present in 8 individuals. Other ECG abnormalities included 3 patients with atrial fibrillation, 3 with first-degree heart block, and 2 with short PR intervals without delta waves. One asymptomatic individual also had pathologic Q waves consistent with apical infarction. Disease progression was slow in the affected individuals, with increasing symptoms of angina and dyspnea; some elderly family members developed congestive heart failure in the context of atrial fibrillation, but none had a myocardial infarction, history of life-threatening arrhythmia, or sudden cardiac death.

Mapping

Mogensen et al. (1999) performed linkage analysis in a large family with hypertrophic cardiomyopathy and excluded linkage to known CMH loci, with lod scores varying from -2.5 to -6.0. Further linkage analysis of plausible candidate genes highly expressed in the human heart yielded a maximum lod score of 3.6 at ACTC1.

Molecular Genetics

In a large 3-generation family with hypertrophic cardiomyopathy, Mogensen et al. (1999) identified heterozygosity for a missense mutation in the ACTC1 gene (102540.0003). The 13 affected family members had diverse phenotypes with variable age of onset and low morbidity; only 3 mutation-positive individuals had symptoms of the disease, although some of the others had abnormal electrocardiograms and most had a septal bulge in the left ventricular outflow tract. One woman had recurrent episodes of palpitations and syncope at 32 years of age and was diagnosed with Wolff-Parkinson-White syndrome (194200); an echocardiogram showed borderline hypertrophy which enlarged significantly over the next 7 years, from 12 mm to 19 mm. One boy had early onset of disease, presenting at 4 years of age with a heart murmur caused by a septal bulge. Only 1 mutation-positive family member was nonpenetrant, an asymptomatic 28-year-old man with no evidence of cardiac disease on ECG or echocardiogram.

Olson et al. (2000) screened the ACTC1 gene in 368 unrelated patients with sporadic or familial CMH and identified 3 different heterozygous mutations in 2 sporadic patients with apical CMH (102540.0007 and 102540.0008, respectively) and in a 4-generation family segregating autosomal dominant CMH (E101K; 102540.0009).

In affected members of 2 families segregating autosomal dominant apical CMH over 3 generations, Arad et al. (2005) identified heterozygosity for the E101K mutation in the ACTC1 gene. A shared haplotype was also identified, providing odds greater than 100:1 that E101K represents a founder mutation in the 2 families; however, haplotype data indicated that E101K arose independently in the family reported by Olson et al. (2000).

Monserrat et al. (2007) screened 247 probands with CMH, dilated cardiomyopathy (see CMD1R, 613434), or left ventricular noncompaction (see LVNC4, 613434) for the E101K mutation in the ACTC1 gene and identified the mutation in 4 probands diagnosed with CMH and 1 with LVNC. Of 46 mutation-positive family members, all had increased maximum left ventricular wall thickness, usually with prominent trabeculations and deep invaginations in the thickened segments; 23 patients fulfilled criteria for LVNC, 22 had been diagnosed with apical CMH, and 3 with restrictive cardiomyopathy. Septal defects were identified in 9 mutation carriers from 4 families, including 8 atrial defects (see ASD5; 612794) and 1 ventricular defect, and were absent in relatives without the mutation. Monserrat et al. (2007) concluded that LVNC and CMH may appear as overlapping entities, and that the E101K mutation in ACTC1 should be considered in the genetic diagnosis of LVNC, apical CMH, and septal defects.

In 2 unrelated children with idiopathic cardiac hypertrophy that developed before 15 years of age, who were presumed to have sporadic cardiomyopathy, Morita et al. (2008) identified 2 different missense mutations in the ACTC1 gene (see, e.g., 102540.0004). One of the children also carried a missense mutation in the MYH7 gene (160760), which is known to cause CMH1. The parents were not studied.