Cardiomyopathy, Dilated, 1r

A number sign (#) is used with this entry because this form of dilated cardiomyopathy (CMD1R) is caused by heterozygous mutation in the ACTC1 gene (102540) on chromosome 15q14.

Mutation in the ACTC1 gene has also been associated with left ventricular noncompaction (LVNC4), hypertrophic cardiomyopathy (CMH11; 612098), and atrial septal defects (ASD5; 612794).

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200); for a similar discussion of left ventricular noncompaction, see LVNC1 (604169).

Olson et al. (1998) studied 2 unrelated families with autosomal dominant idiopathic dilated cardiomyopathy (CMD), one of German ancestry and the other of Swedish Norwegian ancestry. Families were phenotypically characterized by echocardiography, with CMD being defined as left ventricular end-diastolic dimension (LVEDD) greater than the 95th percentile for age and body surface area, and shortening fraction less than 28%. Individuals in both families had variable age at diagnosis (1 to 41 years), similar to other CMD families, with age at diagnosis differing by as much as 20 to 50 years. Heart biopsy specimens from the proband of each family revealed histopathologic findings consistent with CMD, showing moderate focal interstitial fibrosis and myocyte hypertrophy, but no evidence of myocarditis or of the myofibrillar disarray seen in hypertrophic cardiomyopathy (CMH).

In affected members of 2 unrelated families with dilated cardiomyopathy, Olson et al. (1998) identified heterozygosity for 2 different mutations in the ACTC1 gene (102540.0001 and 102540.0002, respectively).

Takai et al. (1999) analyzed the ACTC1 gene in 136 Japanese CMD patients, but found no disease-causing mutations. They concluded that mutation in the ACTC1 gene is a rare cause of CMD, at least in Japanese patients.

Mayosi et al. (1999) studied 57 South African patients with dilated cardiomyopathy, 56% of whom were of black African origin. No mutation predicted to produce an alteration in protein was identified in either the skeletal or cardiac actin genes in any patient.

Left Ventricular Noncompaction 4

Monserrat et al. (2007) screened 247 probands with CMD, hypertrophic cardiomyopathy (see CMH11, 612098), or left ventricular noncompaction (LVNC) for the E101K mutation in the ACTC1 gene (102540.0009) and identified the mutation in 4 probands diagnosed with CMH and 1 with LVNC. The 5 mutation-positive families, 2 of which were previously studied by Arad et al. (2005), were all from the same local area in Galicia, Spain, and shared the same 88-bp allele of the intragenic ACTC1 microsatellite marker that cosegregated with disease in the families, suggesting a likely founder effect. All 46 mutation-positive members of the 5 families had increased maximum left ventricular wall thickness, usually with prominent trabeculations and deep invaginations in the thickened segments, and 23 patients fulfilled criteria for LVNC; 22 were diagnosed with apical CMH, and 3 with restrictive cardiomyopathy. Septal defects were identified in 9 mutation carriers from 4 families, including 8 atrial defects 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.

Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in 63 unrelated adult probands with LVNC but no other congenital heart anomalies, and identified the E101K mutation in the ACTC1 gene in a 15-year-old girl and a 38-year-old woman. Both had inherited the mutation from their affected fathers; haplotype analysis excluded a common ancestor. All 4 patients had noncompaction of the apex and midventricular wall. The 15-year-old girl, who was originally diagnosed with CMH, had syncope and hypoxic brain damage and underwent pacemaker implantation; her 58-year-old father had syncope, congestive heart failure (CHF), and pulmonary hypertension (PHT). The 38-year-old woman had CHF and PHT, whereas her 73-year-old father had no cardiovascular complications.