Cardiomyopathy, Dilated, 2b

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-2B (CMD2B) is caused by homozygous mutation in the GATAD1 gene (614518) on chromosome 7q21. One such family has been reported.

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

Clinical Features

Theis et al. (2011) studied a consanguineous family of Norwegian ancestry segregating autosomal recessive dilated cardiomyopathy. The proband was a 74-year-old woman who presented at age 50 with heart failure and cardiomegaly; echocardiography was diagnostic for CMD. Left ventricular endomyocardial biopsy showed moderate myocyte hypertrophy, mild focal interstitial fibrosis, and mild diffuse endocardial fibrosis, consistent with chronic cardiomyopathy. At the time of evaluation, she had New York Heart Association class II heart failure with moderate to severe left ventricular enlargement and an ejection fraction of 25%. A 76-year-old sister was diagnosed at age 53; she underwent pacemaker implantation for persistent atrial fibrillation. She remained in class II heart failure 23 years after diagnosis, with mild left ventricular enlargement and an ejection fraction of 40%. At age 57, a brother was given a diagnosis of idiopathic left ventricular enlargement, and was confirmed to have CMD on follow-up echocardiogram 3 years later. At age 68, he had cardiomegaly and a borderline ejection fraction of 50%; he died of cancer at age 73. Their parents were first cousins who died at ages 91 and 76 years, with no apparent heart disease. The remaining 6 sibs, aged 55 to 81 years, had completely normal echocardiograms and none developed heart failure over 4 to 22 years of follow-up; similarly, CMD was excluded in the 8 children of the affected individuals, and none developed CMD in over 20 years of follow-up.

Mapping

In a consanguineous family of Norwegian ancestry segregating autosomal recessive dilated cardiomyopathy, Theis et al. (2011) performed genomewide linkage analysis and identified a locus on chromosome 7q21 with a peak multipoint lod score of 3.1 between markers D7S669 and D7S515. Haplotype analysis revealed homozygosity for 2 adjacent short tandem repeats in the 3 affected sibs but none of the 6 unaffected sibs, and flanking markers defined a 24-Mb region encompassing 258 genes. High-density homozygosity mapping narrowed the critical interval to a 7.3-Mb region containing 61 candidate genes.

Inheritance

The transmission pattern of dilated cardiomyopathy in the family reported by Theis et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 affected sisters from a consanguineous family of Norwegian ancestry segregating autosomal recessive dilated cardiomyopathy mapping to chromosome 7q21, Theis et al. (2011) performed whole-exome sequencing, followed by an iterative filtering process, and identified a homozygous missense mutation in the GATAD1 gene (614518.0001); analysis of the exome sequencing data did not show any homozygous mutations in the more than 30 genes previously associated with CMD. Their deceased affected brother was also homozygous for the mutation, but their 6 unaffected sibs were either heterozygous or homozygous for the wildtype allele, which was not found in 474 controls of similar ancestry with normal echocardiograms. Screening of GATAD1 in an additional 273 probands with CMD did not reveal any mutations.