Cardiomyopathy, Familial Restrictive, 3

A number sign (#) is used with this entry because of evidence that familial restrictive cardiomyopathy-3 (RCM3) is caused by heterozygous mutation in the TNNT2 gene (191045) on chromosome 1q32.

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

Clinical Features

Peddy et al. (2006) described a previously healthy 12-month-old girl who suffered a cyanotic episode and on electrocardiogram was found to have marked right atrial enlargement and left axis deviation. Echocardiography revealed a structurally normal heart with severely dilated atria, mild to moderate left ventricular systolic dysfunction, and mild right ventricular systolic dysfunction; left ventricular chamber size and wall thickness were normal, with no regional wall motion abnormalities. Over the next several days, she experienced recurrent episodes of sinus bradycardia and tachycardia associated with diffuse ischemic ECG changes and marked hypotension; hemodynamic evaluation by cardiac catheterization confirmed the diagnosis of RCM, with typical square-root sign and elevated atrial and right and left ventricular pressures. Endomyocardial biopsy revealed moderate myocyte hypertrophy with patchy mild interstitial fibrosis, and ultrastructural examination showed abnormally shaped mitochondria and mild dilation of the sarcoplasmic reticulum, with no viral inclusions. The patient required implantation of a ventricular assist device, at which time severe diastolic dysfunction and hypokinesia of the left ventricular apex were noted, with a corrugated and discolored appearance of the ventricular epicardium. She ultimately underwent orthotopic heart transplant; histologic examination of the explanted heart showed significant myocyte disarray and multiple areas of replacement fibrosis.

Molecular Genetics

In a 12-month-old girl with restrictive cardiomyopathy, Peddy et al. (2006) performed direct sequencing of the 8 genes most commonly implicated in hypertrophic cardiomyopathy and identified a 3-bp deletion in the TNNT2 gene (191045.0011). The deletion was not found in either parent, who had normal echocardiograms at ages 28 and 34 years, respectively. The girl also carried a known MYBPC3 (600958) polymorphism, V896M, which was also found in her unaffected father; the authors suggested that the V896M variant may have acted as a modifier, exacerbating the phenotypic expression of the TNNT2 mutation and causing an unusually early onset of RMC.

In a 3-generation family segregating autosomal dominant cardiomyopathy, in which the proband had a restrictive phenotype and relatives had clinical features of restrictive, hypertrophic (CMH2; 115195), and/or dilated cardiomyopathy (CMD1D; 601494), Menon et al. (2008) performed targeted linkage analysis for 9 sarcomeric genes and identified heterozygosity for the I79N mutation in the TNNT2 gene (191045.0001), previously reported by Thierfelder et al. (1994) in a family with hypertrophic cardiomyopathy. The mutation segregated with the disease phenotype and was not found in unaffected individuals. Despite the variable morphology, all affected members of the family exhibited restrictive physiology. There was a high incidence of atrial tachyarrhythmia but no significant ventricular arrhythmia or sudden death in affected members of this family.