Genetic Evaluation of Dilated Cardiomyopathy

Division of Human Genetics, The Ohio State University College of Medicine, Columbus, OH, USA, .
Current Cardiology Reports (Impact Factor: 1.93). 07/2013; 15(7):375. DOI: 10.1007/s11886-013-0375-1
Source: PubMed


Recent advances have expanded our ability to conduct a comprehensive genetic evaluation for dilated cardiomyopathy (DCM). By evaluating recent literature, this review aims to bring the reader up-to-date on the genetic evaluation of DCM. Updated guidelines have been published. Mutations in BAG3, including a large deletion, were identified in 2 % of DCM. Truncating mutations in TTN were reported in 25 % of DCM. Two new genes have been reported with autosomal recessive DCM. These studies illustrate the role of improved technologies while raising the possibility of a complex genetic model for DCM. The inclusion of TTN has led to an increased genetic testing detection rate of 40 %. While our ability to identify disease-causing variants has increased, so has the identification of variants of unknown significance. A genetic evaluation for DCM must therefore address this complexity.

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    • "LQTS is another leading cause of sudden cardiac death in children and its prevalence has been estimated to be as high as 1 in 2000 [7]. Gene sequencing panels currently available can identify mutations in 75% of patients with congenital LQTS [4]. Although the prevalence of congenital LQTS in families with DCM has not been studied, both conditions are most commonly inherited in an autosomal dominant manner. "
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    ABSTRACT: We describe a young girl with dilated cardiomyopathy, long QT syndrome, and possible energy deficiency. Two major sequence changes were identified by whole exome sequencing (WES) and mitochondrial DNA analysis that were interpreted as potentially causative. Changes were identified in the KCNH2 gene and mitochondrial tRNA for cysteine. A variation was also seen in MYPBC3. Since the launch of WES as a clinically available technology in 2010, there has been concern regarding the identification of variants unrelated to the patient's phenotype. However, in cases where targeted sequencing fails to explain the clinical presentation, the underlying etiology could be more complex than anticipated. In this situation, the extensive reach of this tool helped explain both her phenotype and family history.
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    • "This genetic testing is carried out on a panel of about 50 loci and more than one locus can be implicated in the disease [14] suggesting a dose effect, whereby the more DCM alleles an individual carries, the more severe the phenotype [39]. Gene penetrance has also been reported to affect disease expression and severity, and likewise the type of mutation and the specific gene which is affected often lead to differing features, age of onset or severity, and prognosis [49] [50]. "
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    ABSTRACT: Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed.
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    • "Indeed, investigators have begun to refer to these cases as familial dilated cardiomyopathy (FDC) (Judge and Johnson, 2008; Hershberger et al., 2010; Jefferies, 2010). Inheritance can occur in a variety of manners with the most common pattern of inheritance being autosomal dominant (Zeviani et al., 1991; Towbin et al., 1993; Murphy et al., 2004; Morales and Hershberger, 2013). "
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    ABSTRACT: The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene ((Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric proteins there was a considerable amount of genetic heterogeneity in the affected family members. Interestingly, we also found that the levels of BAG3 protein were significantly reduced in the hearts from unrelated patients with end-stage HF undergoing cardiac transplantation when compared with non-failing controls. Diminished levels of BAG3 protein may be associated with both familial and non-familial forms of dilated cardiomyopathy. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2014 · Journal of Cellular Physiology
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