Cardiomyopathy, Dilated, 1m

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1M (CMD1M) is caused by heterozygous mutation in the CSRP3 gene (600824) on chromosome 11p15. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

In 10 patients with CMD, Knoll et al. (2002) reported a clinical phenotype that included chamber dilation, thin ventricular walls, decreased contractility and impaired relaxation, and no evidence of hypertrophic cardiomyopathy. The phenotype was considered consistent with Csrp3-deficient mouse heart.

Mohapatra et al. (2003) described a 2-year-old girl who died after a 2-day illness, in whom autopsy revealed an enlarged and dilated heart with endocardial fibroelastosis (EFE) of the left ventricle. Light microscopy showed myocardial hypertrophy with no evidence of abnormal storage and no inflammatory cells. Her younger brother developed shortness of breath at age 7 months and was found to have an enlarged heart on chest x-ray; an ECG showed signs of left ventricular hypertrophy, and echocardiography demonstrated a dilated left ventricle with an ejection fraction of 20%. At 14 months of age, cardiac biopsy showed EFE with hypertrophy and interstitial fibrosis but no abnormal storage material or inflammatory infiltrates. Electron microscopy revealed abnormalities of the transverse tubules and focal Z disc irregularities. The boy died at 17 months of age due to recurrent congestive heart failure.

Knoll et al. (2002) identified a trp4-to-arg mutation (W4R; 600824.0001) in the CSRP3 gene in 10 patients with CMD. However, Geier et al. (2008) sequenced exons 2 and 3 of the CSRP3 gene in 652 CMD and 354 CMH patients and 533 unrelated controls, and found the W4R variant in 3 CMD patients (0.5%), 2 CMH patients (0.6%), and 2 controls (0.4%). There was no correlation between presence of the W4R variant and severity of disease and/or progression to heart failure in the 2 CMH patients, and both controls harboring the W4R variant (61 and 75 years old, respectively) had a negative family history of heart failure. Geier et al. (2008) concluded that W4R is not sufficient to cause cardiomyopathy.

In 2 sibs who died of dilated cardiomyopathy and who were negative for mutation in 8 known cardiomyopathy genes, Mohapatra et al. (2003) identified heterozygosity for a missense mutation at a highly conserved residue in the CSRP3 gene (K69R; 600824.0005). Although the mutation was not found in the unaffected father or 200 controls, the unaffected mother was found to be a carrier; the authors noted that incomplete penetrance is common in cardiovascular disease.