Cardiomyopathy, Dilated, 1c, With Or Without Left Ventricular Noncompaction

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1C with or without left ventricular noncompaction (CMD1C), left ventricular noncompaction-3 (LVNC3), and familial hypertrophic cardiomyopathy-24 (CMH24) are caused by heterozygous mutation in the LDB3 gene (605906).

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 and familial hypertrophic cardiomyopathy, see LVNC1 (604169) and CMH1 (192600), respectively.

Clinical Features

Xing et al. (2006) reported 2 Japanese families, one with dilated cardiomyopathy and/or left ventricular noncompaction, and the other with isolated LVNC. In the first family, twin sisters presented with isolated LVNC shortly after birth; their father and paternal grandfather were reportedly diagnosed with LVNC and dilated cardiomyopathy. In the second family, the male proband was diagnosed with isolated LVNC and Wolff-Parkinson-White syndrome (WPW; 194200) on routine physical examination at 13 years of age; his asymptomatic mother was found to have LVNC on echocardiography. A maternal aunt died at 10 years of age of indistinct cardiac disease.

Theis et al. (2006) reported 6 unrelated patients with CMH who were diagnosed in the third to seventh decades of life and who had maximum left ventricular wall thicknesses ranging from 13 to 27 mm; all but 1 had a sigmoid septal shape. Two of the patients underwent myectomy, with moderate to marked myocyte hypertrophy, mild to moderate endocardial fibrosis, and focal myocyte disarray noted on histopathologic examination. Only 1 patient had a family history of CMH, and none of the 6 had a family history of sudden cardiac death.

Mapping

Bowles et al. (1996) found linkage between familial autosomal dominant dilated cardiomyopathy and markers at 10q21-q23 in a family in which 12 of 26 members were affected.

Molecular Genetics

Vatta et al. (2003) screened the LDB3 gene in 100 probands with dilated cardiomyopathy (CMD), 15 of whom also had left ventricular noncompaction (LVNC). They identified heterozygous missense mutations in 2 families, one with CMD and left ventricular hypertrophy (LVH) and the other with CMD, severe LVH, and LVNC (605906.0004 and 605906.0005, respectively), and 4 sporadic patients, 1 with CMD and LVH (605906.0008) and 3 with CMD and LVNC, 1 of whom also had severe LVH (605906.0006 and 605906.0007, respectively).

Arimura et al. (2004) analyzed the LDB3 gene in 96 unrelated Japanese patients with dilated cardiomyopathy who were negative for mutation in 11 other cardiomyopathy-associated genes and identified a missense mutation (605906.0009) in a 61-year-old man; his affected brother and sister also carried the mutation as did an unaffected sister. An older brother had died suddenly at age 51 and another brother died of CMD at age 61. Development of disease occurred relatively late in this family: after 50 years of age in the 4 affected brothers, and at 69 years of age in their affected sister. The authors noted that the 65-year-old mutation-positive unaffected sister might yet develop disease. There were no signs of skeletal muscle involvement in these patients and no evidence of a primary conduction defect on electrocardiogram. The mutation was not found in 2 unaffected brothers or in 400 unrelated healthy controls.

In 4 affected members of 2 unrelated Japanese families with LVNC, Xing et al. (2006) identified heterozygosity for a 1876G-A transition in exon 15 of LDB3, resulting in the D626N substitution. The mutation was not found in 200 controls. In the first family, twin sisters presented with isolated LVNC shortly after birth; their father and paternal grandfather were reportedly diagnosed with LVNC and dilated cardiomyopathy, but DNA was not available for study. In the second family, the male proband was diagnosed with isolated LVNC and Wolff-Parkinson-White syndrome (WPW; 194200) on routine physical examination at 13 years of age; his asymptomatic mutation-positive mother was found to have LVNC on echocardiography. A maternal aunt died at 10 years of age of indistinct cardiac disease.

In a cohort of 239 patients with CMH who were negative for mutation in the 8 most common CMH-associated myofilament genes, Theis et al. (2006) analyzed 5 candidate Z-disc genes and identified 14 mutations in 13 patients, including 5 different heterozygous missense mutations in the LDB3 gene in 6 unrelated patients (see, e.g., 605906.0005 and 605906.0010). The authors observed that 11 (85%) of the 13 patients with Z-disc-associated CMH had a sigmoidal septal contour, in contrast to the reverse septal curvature seen with myofilament-associated CMH.

Levitas et al. (2016) studied 2 large Bedouin families segregating autosomal dominant CMD and ventricular arrhythmias, with focal LVNC in some patients of the first family and apical trabeculations compatible with a mild variant of LVNC some patients of the second family. Analysis of 100 cardiomyopathy-associated genes revealed only 1 putative mutation, the D117N variant in the LDB3 gene (605906.0007). However, the variant was present in only 6 of 16 genotyped patients, and was also detected in 5 healthy family members who were thoroughly evaluated. In addition, there was no apparent correlation between disease severity and the presence of D117N. The variant was present in heterozygosity in 11 (5.2%) of 210 chromosomes from unrelated individuals from the general Bedouin population from the same region of southern Israel, which was much higher than the incidence of idiopathic CMD in that population. Levitas et al. (2016) concluded that, at least in the Bedouin population, D117N is not the causative mutation for these cardiac abnormalities, and suggested that it may not be causative in other patients as well.