Cardiomyopathy, Familial Hypertrophic, 25

A number sign (#) is used with this entry because of evidence that hypertrophic cardiomyopathy-25 (CMH25) is caused by heterozygous mutation in the TCAP gene (604488) on chromosome 17q12.

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

Clinical Features

Hayashi et al. (2004) studied 2 Japanese families with hypertrophic cardiomyopathy. In the first family, an affected mother and son both showed left ventricular hypertrophy (LVH) on electrocardiography (ECG), and the 62-year-old mother also exhibited Wolff-Parkinson-White syndrome (see 194200) whereas her 29-year-old son had abnormal Q-waves. The mother's father had died suddenly after exercise at 34 years of age. In the second family, a 67-year-old sister and 48-year-old brother had CMH; the sister showed LVH on ECG, whereas the brother had abnormal Q-waves. Two of their sibs had died suddenly after exercise, at 33 and 44 years of age.

Bos et al. (2006) reported a 65-year-old woman who was diagnosed with CMH at 44 years of age and who had massive hypertrophy, with a maximum left ventricular wall thickness of 46 mm. Although she was asymptomatic at presentation, she later developed dyspnea. She was treated with myectomy and a pacemaker. Family history included CMH but not sudden cardiac death. Reporting on the same patient, Theis et al. (2006) noted that she exhibited a sigmoid septal shape and that histopathologic examination of cardiac tissue from the myectomy procedure showed severe myocyte hypertrophy with moderate interstitial fibrosis.

Molecular Genetics

Following a screen of 10 known CMH-associated genes in 346 patients with CMH, Hayashi et al. (2004) directly sequenced the TCAP gene and identified heterozygosity for 2 different TCAP missense mutations, T137I (604488.0004) and R153H (604488.0005), in 2 Japanese probands who were negative for mutation in the known genes. The mutations, which segregated with disease in each family, were not found in 240 Japanese and 70 Korean controls.

In a cohort of 389 unrelated patients with CMH, Bos et al. (2006) screened for mutations in the 8 CMH-associated myofilament genes and in the 3 Z-disc genes TTN (188840), CSRP3 (600824), and TCAP. A variant was detected in the TCAP gene in 4 of the patients (see, e.g., R70W; 604488.0006).

Dilated Cardiomyopathy 1N

In a patient with dilated cardiomyopathy, previously designated in OMIM as CMD1N, Knoll et al. (2002) identified a heterozygous mutation (R87Q; 604488.0003) in the TCAP gene. Based on limited evidence of pathogenicity, this variant has been reclassified as a variant of unknown significance.