Cardiomyopathy, Dilated, 1y

A number sign (#) is used with this entry because dilated cardiomyopathy-1Y (CMD1Y) and left ventricular noncompaction-9 (LVNC9) are caused by heterozygous mutation in the TPM1 gene (191010) on chromosome 15q22.1.

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

Description

Dilated cardiomyopathy-1Y (CMD1Y) is characterized by severe progressive cardiac failure, resulting in death in the third to sixth decades of life in some patients. Electron microscopy shows an abnormal sarcomere structure (Olson et al., 2001).

In left ventricular noncompaction-9 (LVNC9), patients may present with cardiac failure or may be asymptomatic. Echocardiography shows noncompaction of the apex and midventricular wall of the left ventricle (Probst et al., 2011). Some patients also exhibit Ebstein anomaly of the tricuspid valve (Kelle et al., 2016) and some have mitral valve insufficiency (Nijak et al., 2018).

Clinical Features

Olson et al. (2001) described 2 probands with familial dilated cardiomyopathy. One was a 27-year-old man whose father and paternal uncle died from heart failure at age 27 and 49 years, respectively. Because of suspected familial CMD, screening echocardiogram was performed when the proband was 17 years old but was reportedly normal. At 26 years of age, the proband developed shortness of breath, edema, and nonsustained ventricular tachycardia. He had no echocardiographic features of hypertrophic cardiomyopathy, coronary arteries were normal by angiography, and cardiac biopsy findings were nonspecific and consistent with idiopathic CMD. Despite aggressive medical therapy and implantation of an automatic cardioverter defibrillator, he died at age 27 while on a cardiac transplant waiting list. The second proband presented at 3 months of age with congestive heart failure and was diagnosed with idiopathic CMD based on echocardiographic findings; her heart failure progressed while on medical therapy and she underwent cardiac transplantation at 10 years of age. Electron microscopy of her explanted heart tissue revealed an abnormal sarcomere structure in which the thin filaments of many sarcomeres appeared irregular and fragmented; the sarcomeres were also contracted with decreased distance between Z bands and the sarcolemma had a scalloped appearance. The girl's mother, who had developed heart palpitations during pregnancy that recurred 6 months after delivery, was diagnosed with idiopathic CMD at 33 years of age based on echocardiographic and cardiac biopsy findings and the absence of coronary artery disease on angiography. She remained stable on minimal medical therapy. Family history included a maternal grandfather who had died at 59 years of age from presumed myocardial infarction, and his father and several sibs reportedly died in their 50s from heart disease.

Left Ventricular Noncompaction 9

Probst et al. (2011) described 2 white families of western European descent with left ventricular noncompaction (LVNC) due to mutations in the TPM1 gene (see MOLECULAR GENETICS). In the first family, the proband was a man who presented at 63 years of age with congestive heart failure and was found to have noncompacted segments of the apex and midventricular wall, with a left ventricular ejection fraction (LVEF) of 19% and left ventricular fractional shortening (LVFS) of 18%. He had 2 affected asymptomatic children, a 32-year-old daughter and a 34-year-old son, who were identified only by family screening and were found to have noncompacted apical segments by echocardiography, with an LVEF of 37% and 53% and an LVFS of 20% and 32%, respectively. In addition, a granddaughter had congestive heart failure and atrial fibrillation that was believed to be due to myocarditis, for which she underwent cardiac transplantation at age 5 years. She was diagnosed with dilated cardiomyopathy without signs of LVNC. A myocardial tissue sample from the explanted left ventricular apex revealed pronounced endomyocardial fibroelastosis and minimal interstitial fibrosis. In the second family, the 55-year-old male proband presented with chest pain and dyspnea, and echocardiography revealed pronounced LVNC of the apex and midventricular wall, with increased right ventricular trabeculations. Cardiac MRI showed normal left ventricular (LV) mass and extensive diffuse fibrosis of the LV, predominantly located on the epicardium and extending transmurally into the anterior and inferior LV wall. The hypertrophic interventricular septum was spared and showed no recesses or prominent trabeculations. Family history revealed that the proband's father had died from heart disease at age 60 and an uncle had a sudden cardiac death at age 40.

Kelle et al. (2016) reported a 2-year-old girl who presented at birth with heart failure and was found to have severe Ebstein anomaly (EA) of the tricuspid valve as well as LVNC. At age 2 years, chest x-ray showed massive cardiomegaly, and echocardiography revealed apical displacement of the tricuspid valve annulus with tethering of the septal leaflet and a large coaptation gap, resulting in severe tricuspid regurgitation. Cardiac MRI confirmed LVNC and globally reduced ventricular systolic function, with ejection fractions of 33% on the right and 20% on the left. Due to severe left ventricular dysfunction and pulmonary hypertension, she was not a candidate for repair of EA; she died following a cardiac catheterization procedure, from presumed pulmonary hemorrhage. Autopsy findings were unavailable at the time of the report.

Nijak et al. (2018) studied a family in which 2 sisters had LVNC and EA. The more severely affected sister developed progressive heart failure and died at age 3.5 years, while awaiting transplantation. Her younger sister, who also had mild mitral valve insufficiency, maintained normal left ventricular function on ACE (106180) inhibitors. Their father was evaluated after his daughters were diagnosed; MRI at age 33 showed LVNC and a mildly dilated left atrium, with normal left ventricular function. The father's male cousin had been diagnosed with LVNC and mitral insufficiency as a neonate, and the cousin had a son with LVNC, who also had progressive mitral insufficiency and pulmonary hypertension and underwent mitral valve replacement at age 3.5 years.

Molecular Genetics

In affected individuals from 2 unrelated families with idiopathic dilated cardiomyopathy, Olson et al. (2001) identified heterozygosity for missense mutations in the TPM1 gene: E54K (191010.0004) and E40K (191010.0005).

Left Ventricular Noncompaction 9

In a cohort of 63 unrelated white patients of western European descent with left ventricular noncompaction, Probst et al. (2011) analyzed 8 sarcomere genes and identified 2 probands with heterozygous missense mutations in the TPM1 gene (191010.0006 and 191010.0007).

In a 2-year-old girl with LVNC and Ebstein anomaly, Kelle et al. (2016) screened 38 CMD- or LVNC-associated genes and identified heterozygosity for a de novo missense mutation in the TPM1 gene (D159N; 191010.0008). The authors stated that the mutation had been previously identified in a patient with dilated cardiomyopathy, although it was not reported in the published literature.

In a family with LVNC with or without Ebstein anomaly and/or mitral valve insufficiency, Nijak et al. (2018) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the TPM1 gene (L113V; 191010.0009) that segregated with disease and was not found in public variant databases.