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      Inherited Cardiomyopathies: Genetics and Clinical Genetic Testing

      , MD, PhD 1 , , MD, PhD 1 , , PhD 1 , , MD, PhD 1 , , MD, PhD , 1

      Cardiovascular Innovations and Applications

      Compuscript

      Genetics, HCM, DCM, RCM, ARVD/C, LVNC

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          Abstract

          Inherited cardiomyopathies are major causes of morbidity and mortality and include a group of cardiac disorders such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), left ventricular noncompaction (LVNC), and restrictive cardiomyopathy (RCM). These diseases have a substantial genetic component and predispose to sudden cardiac death. Since the first gene was identified as a disease-causing gene for HCM over two decades ago, more than eighty genes have been identified to be associated with inherited cardiomyopathies and genetic testing has become prevalent in making clinical diagnosis. With the advent of next-generation sequencing technology, genetic panel testing of inherited cardiomyopathies has become feasible and cost efficient. In this review, we summarize the individual cardiomyopathies with the emphasis on cardiomyopathy genetics and genetic testing.

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          Most cited references 41

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          Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

          Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with nonsyndromic presentations from a broad referral population over 10 years.
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            Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing

            Background Clinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of a HTS strategy for patients with hypertrophic cardiomyopathy (HCM) using a targeted HTS methodology and workflow developed for patients with a range of inherited cardiovascular diseases. By comparing the sequencing results with published findings and with sequence data from a large-scale exome sequencing screen of UK individuals, we sought to quantify the strength of the evidence supporting causality for detected candidate variants. Methods and results 223 unrelated patients with HCM (46±15 years at diagnosis, 74% males) were studied. In order to analyse coding, intronic and regulatory regions of 41 cardiovascular genes, we used solution-based sequence capture followed by massive parallel resequencing on Illumina GAIIx. Average read-depth in the 2.1 Mb target region was 120. Rare (frequency<0.5%) non-synonymous, loss-of-function and splice-site variants were defined as candidates. Excluding titin, we identified 152 distinct candidate variants in sarcomeric or associated genes (89 novel) in 143 patients (64%). Four sarcomeric genes (MYH7, MYBPC3, TNNI3, TNNT2) showed an excess of rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in cases compared to controls. The estimated probability that a nsSNP in these genes is pathogenic varied between 57% and near certainty depending on the location. We detected an additional 94 candidate variants (73 novel) in desmosomal, and ion-channel genes in 96 patients (43%). Conclusions This study provides the first large-scale quantitative analysis of the prevalence of sarcomere protein gene variants in patients with HCM using HTS technology. Inclusion of other genes implicated in inherited cardiac disease identifies a large number of non-synonymous rare variants of unknown clinical significance.
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              The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy.

              Left ventricular (LV) noncompaction (LVNC) is a distinct cardiomyopathy featuring a thickened bilayered LV wall consisting of a thick endocardial layer with prominent intertrabecular recesses with a thin, compact epicardial layer. Similar to hypertrophic and dilated cardiomyopathy, LVNC is genetically heterogeneous and was recently associated with mutations in sarcomere genes. To contribute to the genetic classification for LVNC, a systematic cardiological family study was performed in a cohort of 58 consecutively diagnosed and molecularly screened patients with isolated LVNC (49 adults and 9 children). Combined molecular testing and cardiological family screening revealed that 67% of LVNC is genetic. Cardiological screening with electrocardiography and echocardiography of 194 relatives from 50 unrelated LVNC probands revealed familial cardiomyopathy in 32 families (64%), including LVNC, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Sixty-three percent of the relatives newly diagnosed with cardiomyopathy were asymptomatic. Of 17 asymptomatic relatives with a mutation, 9 had noncompaction cardiomyopathy. In 8 carriers, nonpenetrance was observed. This may explain that 44% (14 of 32) of familial disease remained undetected by ascertainment of family history before cardiological family screening. The molecular screening of 17 genes identified mutations in 11 genes in 41% (23 of 56) tested probands, 35% (17 of 48) adults and 6 of 8 children. In 18 families, single mutations were transmitted in an autosomal dominant mode. Two adults and 2 children were compound or double heterozygous for 2 different mutations. One adult proband had 3 mutations. In 50% (16 of 32) of familial LVNC, the genetic defect remained inconclusive. LVNC is predominantly a genetic cardiomyopathy with variable presentation ranging from asymptomatic to severe. Accordingly, the diagnosis of LVNC requires genetic counseling, DNA diagnostics, and cardiological family screening.
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                Author and article information

                Journal
                CVIA
                Cardiovascular Innovations and Applications
                CVIA
                Compuscript (Ireland )
                2009-8782
                2009-8618
                February 2017
                June 2017
                : 2
                : 2
                : 297-308
                Affiliations
                1John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
                Author notes
                Correspondence: Yuxin Fan, MD, PhD, John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, 1102 Bates Ave, Suite 430.09, Houston, TX 77030, USA, Tel.: 832-824-4155, Fax: 832-825-5159, E-mail: yuxinf@ 123456bcm.edu
                Article
                cvia20170015
                10.15212/CVIA.2017.0015
                Copyright © 2017 Cardiovascular Innovations and Applications

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 Unported License (CC BY-NC 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc/4.0/.

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