Cardiomyopathy, Dilated, 1d

A number sign (#) is used with this entry because familial dilated cardiomyopathy mapping to 1q32 was shown to result from heterozygous mutation in the gene encoding cardiac troponin T (TNNT2; 191045) on chromosome 1q32.

Mutation in the TNNT2 gene has also been associated with left ventricular noncompaction (LVNC6), hypertrophic cardiomyopathy (CMH2; 192600), and restrictive cardiomyopathy (RCM3; 612422).

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).

Clinical Features

Kamisago et al. (2000) studied families with dilated cardiomyopathy. In 1 family (family C), sudden death occurred in a 26- and a 27-year-old as well as in a 1- and an 8-month-old, both of whom had a diagnosis of infantile cardiomyopathy. In another family (family D), a 19-year-old female had postpartum congestive heart failure, resulting in sudden death. Her son died of congestive heart failure at the age of 15 years; postmortem showed marked right ventricular dilatation and normal cardiac ultrastructure. Her 17-year-old sister had died of congestive heart failure, and postmortem showed marked dilatation of the right and left ventricles with histologic findings of increased interstitial fibrosis without myocyte disarray.

Left Ventricular Noncompaction

Luedde et al. (2010) reported a Caucasian family in which the proband was a 52-year-old woman who presented with exercise-related dyspnea and impaired left ventricular systolic function. Echocardiography revealed typical signs of left ventricular noncompaction (LVNC), with prominent trabeculations and intertrabecular recesses which were perfused on color Doppler imaging. Cardiac MRI confirmed that the segments of noncompacted myocardium primarily involved the apical, lateral, and inferior wall of the left ventricle and showed a 2-layered structure with a ratio greater than 2.3 between the noncompacted subendocardial layer and the compacted subepicardial layer at end diastole. Family history revealed that 3 of her 4 children had died at less than 1 year of age, with 1 death related to a dilated heart with a reported diagnosis of cardiac fibroelastosis, and the other 2 of unknown cause. A 5-month-old granddaughter had recently been diagnosed with decompensated heart failure and was found to have LVNC on echocardiography, with numerous deep trabeculations of the inferior, apical, and lateral walls of the left ventricle, and the 2-layered structure of the myocardium typical for LVNC. Due to rapid disease progression, she underwent heart transplantation at 26 months of age; tissue sections of the explanted heart showed typical features of LVNC, including intertrabecular recesses with enhanced fibrosis of the myocardial layer. Evaluation of her asymptomatic father, the son of the proband, revealed moderately reduced left ventricular function with noncompacted myocardium and regional hypokinesia, primarily in the apical and inferior regions.

Mapping

Schultz et al. (1995) showed that genetic heterogeneity exists in pure familial dilated cardiomyopathy, which was confirmed by Durand et al. (1995). Durand et al. (1995) studied a family residing in California and Utah with dilated cardiomyopathy in multiple members of 3 generations and by implication a fourth. Linkage analysis with a large number of markers mapped the locus to 1q32, with a peak multipoint lod score of 6.37 at D1S414.

Molecular Genetics

In 2 unrelated families with familial dilated cardiomyopathy, Kamisago et al. (2000) found a 3-bp deletion in the TNNT2 gene resulting in the elimination of 1 of 4 lysine residues encoded in tandem in exon 13 (191045.0006). Haplotype analyses indicated that each mutation arose independently in these families.

Li et al. (2001) refined the critical region in the family originally studied by Durand et al. (1995) and amplified and directly sequenced cDNA or genomic exons from candidate genes within the region. They identified an arg141-to-trp (R141W) mutation in the TNNT2 gene (191045.0007). This sequence change cosegregated with dilated cardiomyopathy in the family, with 5 phenotypically normal mutation carriers in addition to 14 affected individuals. Evaluation of 200 control chromosomes and 219 individuals with familial hypertrophic cardiomyopathy (CMH; see 192600) failed to detect the variation, leading the authors to conclude that this was a pathogenic mutation.

Mogensen et al. (2004) analyzed the TNNT2 gene in 235 consecutive unrelated probands with dilated cardiomyopathy and identified 4 different mutations in 4 families (see 191045.0006 and 191045.0008-191045.0010). Histologic examination of specimens from 2 antemortem biopsies, 1 autopsy heart, and 3 explanted hearts showed nonspecific abnormalities including myocyte hypertrophy, increased interstitial fibrosis, and endocardial thickening with smooth muscle cells characteristic of CMD; there was no significant myocyte disarray characteristic of CMH or features suggesting storage disease.

In a 3-generation family segregating autosomal dominant cardiomyopathy, in which the proband had a restrictive phenotype (RCM3; 612422) and relatives had clinical features of restrictive, hypertrophic (CMH2; 115195), and/or dilated cardiomyopathy, 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.

Left Ventricular Noncompaction

In a 20-year-old woman who presented in cardiogenic shock and was diagnosed with isolated left ventricular noncompaction (LVNC), Klaassen et al. (2008) identified heterozygosity for a de novo missense mutation in the TNNT2 gene (R131W; 191045.0008). The patient had primarily midlateral and midinferior LVNC, left ventricular dilation, and impaired left ventricular systolic function. Cardiovascular complications included congestive heart failure and transient ischemic attacks.

In a 3-generation family with autosomal dominant left ventricular noncompaction of variable severity, Luedde et al. (2010) analyzed 6 cardiomyopathy-associated genes and identified a heterozygous missense mutation in the TNNT2 gene (E96K; 191045.0012) that segregated fully with disease. Chorionic villus biopsy of a subsequent pregnancy in the family showed that the fetus carried the mutation, and soon after birth the infant boy showed clinical signs of heart failure as well as decreased left ventricular function on echocardiography. Transgenic mice with the E96K mutation developed left ventricular dysfunction and showed induction of markers of heart failure, but LVNC was not observed. Luedde et al. (2010) noted that their animal data supported the concept of LVNC as a secondary consequence of genetic alteration, and they suggested that it might be problematic to consistently delineate LVNC from other cardiomyopathies.