![]() 6 The majority of DCM genes have been discovered by targeted DNA sequence analyses of candidate genes. 7 Since 1993, pathogenic mutations in >30 genes have been identified in patients with DCM, yet mutations in these genes are estimated to account for only one third of cases. 6 Moreover, recognition of DCM as a heritable condition has been the impetus for human genetic investigations to uncover the molecular bases of myopathic heart failure. Idiopathic dilated cardiomyopathy (DCM) is a familial disorder in 20% to 48% of cases, 1 – 5 providing a rationale for screening echocardiography in at-risk relatives to detect presymptomatic disease. Immunohistochemistry demonstrated nuclear localization of GATAD1 in left ventricular myocytes, yet subcellular expression and nuclear morphology were aberrant in the proband. Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages. The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched controls, altered a conserved residue of GATAD1, encoding GATA zinc finger domain-containing protein 1. An iterative bioinformatics process was used to filter >40 000 genetic variants, revealing a single shared homozygous missense mutation localized to the 7q21 critical region. Exome sequencing of the affected sisters was then used as a complementary strategy for mutation discovery. Genotyping and linkage analysis mapped an AR DCM locus to chromosome arm 7q21, which was validated and refined by high-density homozygosity mapping. Customer Service and Ordering InformationĮchocardiography in 17 adult descendants of first cousins revealed DCM in 2 female siblings and idiopathic left ventricular enlargement in their brother.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).
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