Whole-exome sequencing of cases with familial cardiomyopathy
type: CreativeWork
description: Introduction: Cardiomyopathies are disorders of the myocardium that can lead to heart failure, arrhythmias and sudden death. Heritable forms include dilated, hypertrophic and arrhythmogenic cardiomyopathy (DCM, HCM and ACM respectively). As heterogeneous disorders, over 50 genes have been implicated in these cardiomyopathies to date. However, the yield of genetic testing ranges from less than 40% in idiopathic DCM to over 50% in ACM and HCM, indicating that many causal genes are yet to be identified. This is particularly true in African populations, where the genetics of cardiomyopathy is underexplored. In a review of the role of next-generation sequencing in gene discovery, over 20 new cardiomyopathy genes were found to have been identified through exome sequencing of cardiomyopathy patients. The literature review also highlighted the need for functional validation of newly identified disease genes. Therefore, the aims of this investigation were to utilise exome sequencing to identify disease-causing mutations in South African families with heritable cardiomyopathy, and to establish methods of variant validation through functional modelling in zebrafish. Methods: Five probands and 34 relatives were included in this investigation. The probands and their relatives were clinically examined and diagnosed with DCM, HCM or ACM at Groote Schuur Hospital, Cape Town. Exome sequencing was performed on each of the five probands as well as at least one other family member. Variants of interest were identified by filtering the exome sequencing data by allele frequency, variant quality, variant consequence, predicted deleteriousness, and the potential inheritance patterns as determined by family history analysis. Variants occurring in known cardiomyopathy genes were prioritised, but genes outside the cardiac panel were considered based on literature mining, expression in the heart, and results of prior animal models. Candidate variants were validated by Sanger sequencing and ass…
abstract: Introduction: Cardiomyopathies are disorders of the myocardium that can lead to heart failure, arrhythmias and sudden death. Heritable forms include dilated, hypertrophic and arrhythmogenic cardiomyopathy (DCM, HCM and ACM respectively). As heterogeneous disorders, over 50 genes have been implicated in these cardiomyopathies to date. However, the yield of genetic testing ranges from less than 40% in idiopathic DCM to over 50% in ACM and HCM, indicating that many causal genes are yet to be identified. This is particularly true in African populations, where the genetics of cardiomyopathy is underexplored. In a review of the role of next-generation sequencing in gene discovery, over 20 new cardiomyopathy genes were found to have been identified through exome sequencing of cardiomyopathy patients. The literature review also highlighted the need for functional validation of newly identified disease genes. Therefore, the aims of this investigation were to utilise exome sequencing to identify disease-causing mutations in South African families with heritable cardiomyopathy, and to establish methods of variant validation through functional modelling in zebrafish. Methods: Five probands and 34 relatives were included in this investigation. The probands and their relatives were clinically examined and diagnosed with DCM, HCM or ACM at Groote Schuur Hospital, Cape Town. Exome sequencing was performed on each of the five probands as well as at least one other family member. Variants of interest were identified by filtering the exome sequencing data by allele frequency, variant quality, variant consequence, predicted deleteriousness, and the potential inheritance patterns as determined by family history analysis. Variants occurring in known cardiomyopathy genes were prioritised, but genes outside the cardiac panel were considered based on literature mining, expression in the heart, and results of prior animal models. Candidate variants were validated by Sanger sequencing and ass…
author: Spracklen, Timothy
keywords: medicine
date published: 2021
date modified: 2026-07-22T22:23:24Z
provider: University of Cape Town
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Department of Medicine

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property ID: Handle
value: http://hdl.handle.net/11427/33999