Analysis of genetic variations associated with arrhythmogenic right ventricular cardiomyopathy
Doctoral Thesis
2016
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University of Cape Town
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Cardiomyopathy accounts for 20-30% of acute heart failure cases in adult Africans. Several types of cardiomyopathy have been identified; this study focused primarily on the genetic causes of arrhythmogenic right ventricular cardiomyopathy (ARVC). Many genes are implicated in ARVC pathogenesis, but many remain to be identified. We investigated a South African family (ACM2) with autosomal dominant ARVC, for whom the genetic cause of disease was unknown. Extensive genetic analysis was previously performed using genome-wide linkage analysis, but no disease-causing genetic variant was identified. We subsequently performed candidate gene screening of the phospholamban (PLN) gene, genome-wide copy number variant (CNV) analysis and whole exome sequencing to identify the causal genetic variant. The ACM2 family harboured no disease-causing PLN variants. However, on screening all cardiomyopathy cases in our registry (ARVC, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy and peripartum cardiomyopathy), we identified a known pathogenic PLN variant (c.25C>T; p.R9C) in a DCM family of European descent. This variant was reported in an American DCM family of European descent. Haplotype analysis revealed independent variant origins in these families. CNV analysis revealed no disease-causing variants in the ACM2 family. Whole exome sequencing of two affected ACM2 family members revealed 38 variants shared by these individuals. Variants were verified in family members and population controls by high resolution melt analysis and Sanger sequencing, and by bioinformatics analysis to predict variant pathogenicity. A novel N-cadherin (CDH2) c.686A>C (p.Q229P) variant segregated with ARVC in the ACM2 family and was bioinformatically predicted to be deleterious. An additional pathogenic CDH2 variant (c.1219G>A (p.D407N)) was identified in another individual with ARVC after screening 85 cases. These CDH2 variants were absent in normal population controls. Furthermore, alterations in Cdh2 are known to cause cardiomyopathy in rodent models. Taken together, these findings support the causal role of N-cadherin gene variants in human cardiomyopathy.
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Fish, M. 2016. Analysis of genetic variations associated with arrhythmogenic right ventricular cardiomyopathy. University of Cape Town.