Cardiomyopathy, Familial Hypertrophic, 26

A number sign (#) is used with this entry because of evidence that familial cardiomyopathy of the hypertrophic (CMH26) or restrictive (RCM5) type is caused by heterozygous mutation in the FLNC gene (102565) on chromosome 7q32.

For a general phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600); for familial restrictive cardiomyopathy, see RCM1 (115210).

Clinical Features

Hypertrophic Cardiomyopathy

Valdes-Mas et al. (2014) studied a 4-generation Spanish family segregating autosomal dominant hypertrophic cardiomyopathy, in which the proband was diagnosed at age 20 years, based on electrocardiography (ECG) showing left ventricular hypertrophy due to volume overload and echocardiography showing a 27-mm hypertrophic septum. At age 32, she developed atrial fibrillation; MRI showed extensive areas of fibrosis involving the septum, apex, and anterior wall, and she received an implantable cardioverter defibrillator. At age 53, she was functionally grade I in the New York Heart Association classification, with a left ventricular outflow obstruction of 30 mm Hg. She had 2 affected maternal cousins, 1 who was diagnosed at age 45 with heart failure, left ventricular volume overload (LVVO), and a 21-mm hypertrophic septum, and the other, who was diagnosed at age 82, was asymptomatic but showed LVVO with a 15-mm septum. In addition, the proband's mother died suddenly at age 34, and her maternal grandmother and great-aunt died at ages 62 and 55, respectively, from cardiac causes.

Restrictive Cardiomyopathy

Brodehl et al. (2016) studied 2 Canadian families segregating autosomal dominant restrictive cardiomyopathy in which almost all affected individuals had normal contractility, with normal left ventricular wall thickness and systolic function, but showed various degrees of diastolic dysfunction and pulmonary hypertension, as well as left or biatrial enlargement. Atrial fibrillation was common, and significant conduction disease requiring pacemakers was common in 1 of the families. There was no clinically detectable skeletal involvement, and CK levels were in the normal or slightly elevated range. Tissue analysis of several biopsies and heart explants consistently demonstrated mild to moderate myocyte hypertrophy, interstitial fibrosis, and only mild myocyte disarray. In addition, explanted heart tissue showed eosinophilic cytoplasmic inclusions in the free left ventricular wall, and electron microscopy revealed disorganization of Z-bands and abnormal accumulations of filamentous material in occasional fibers of the left ventricle.

Inheritance

The transmission pattern of cardiomyopathy in the families reported by Valdes-Mas et al. (2014) and Brodehl et al. (2016) was consistent with autosomal dominant inheritance.

Molecular Genetics

In the proband from a 4-generation Spanish family with hypertrophic cardiomyopathy, who was negative for mutation in 9 CMH-associated sarcomeric genes, Valdes-Mas et al. (2014) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the FLNC gene (A1539T; 102565.0005). The mutation segregated with disease in the family and was not found in more than 400 Spanish controls or in the 1000 Genomes Project or Exome Sequencing Project databases. Sequencing of FLNC in 92 probands with CMH identified 7 more heterozygous mutations in 8 patients (see, e.g., 102565.0006 and 102565.0007). The FLNC variants showed strong cosegregation with disease in the families, with 14 of 16 mutation carriers over 40 years of age exhibiting symptoms of CMH, for a penetrance of more than 87%.

In a Canadian family with restrictive cardiomyopathy, Brodehl et al. (2016) analyzed 90 cardiomyopathy-associated genes and identified heterozygosity for a missense mutation in the FLNC gene (S1624L; 102565.0008). Whole-exome sequencing in an unrelated Canadian family with RCM revealed heterozygosity for a different missense mutation in FLNC (I2160F; 102565.0009). Each mutation segregated fully with disease in the family, and neither was found in controls or public variant databases.