Clinical features, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy in South Africans

Abstract

SummaryBackgroundLittle is known about the clinical characteristics, spectrum of causal genetic mutations and outcome of hypertrophic cardiomyopathy (HCM) in Africans. The objective of this study was to delineate the clinical and genetic features and outcome of HCM in African patients.MethodsInformation on clinical presentation, electrocardiographic and echocardiographic findings, and outcome of cases with HCM was collected from the Cardiac Clinic at Groote Schuur Hospital over a mean duration of follow up of 9.1 ± 3.4 years. Genomic DNA was screened for mutations in 15 genes that cause HCM, i.e. cardiac myosinbinding protein C (MYBPC3), cardiac β-myosin heavy chain (MYH7), cardiac troponin T2 (TNNT2), cardiac troponin I (TNNI3), regulatory light chain of myosin (MYL2), essential light chain of myosin (MYL3), tropomyosin 1 (TPM1), phospholamban (PLN), α-actin (ACTC1), cysteine and glycine-rich protein 3 (CSRP3), AMP-activated protein kinase (PRKAG2), α-galactosidase (GLA), four-and-a-half LIM domains 1 (FHL1), lamin A/C (LMNA) and lysosomeassociated membrane protein 2 (LAMP2). Survival and its predictors were analysed using the Kaplan–Meier and Cox proportional hazards regression methods, respectively.ResultsForty-three consecutive patients [mean age 38.5 ± 14.3 years; 25 (58.1%) male; and 13 (30.2%) black African] were prospectively enrolled in the study from January 1996 to December 2012. Clinical presentation was similar to that reported in other studies. The South African founder mutations that cause HCM were not found in the 42 probands. Ten of 35 index cases (28.6%) tested for mutations in 15 genes had disease-causing mutations in MYH7 (six cases or 60%) and MYBPC3 (four cases or 40%). No disease-causing mutation was found in the other 13 genes screened. The annual mortality rate was 2.9% per annum and overall survival was 74% at 10 years, which was similar to the general South African population. Cox’s proportional hazards regression showed that survival was predicted by New York Heart Association (NYHA) functional class at last visit (p = 0.026), but not by the presence of a disease-causing mutation (p = 0.474).ConclusionsComprehensive genetic screening was associated with a 29% yield of causal genetic mutations in South African HCM cases, all in MYH7 and MBPC3 genes. A quarter of the patients had died after a decade of follow up, with NYHA functional class serving as a predictor of survival.

Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies

“…Mutation screening of PLN in 315 patients with cardiomyopathy (ARVC (n = 111) 14 , DCM (n = 95) 15 , HCM (n = 40) 16 , and peripartum cardiomyopathy (PPCM) (n = 69)) 17 revealed the previously reported c.25C > T (p.R9C) mutation in a proband of European descent with severe DCM (DCM 320.1; Individual II:2) 6 . This mutation results in the alteration of a conserved amino acid ( Fig.…”

“…DCM, PPCM and HCM patients were diagnosed on the basis of the definitions of the European Society of Cardiology 1 . The details on methods of clinical evaluation, demographics and clinical parameters of patients enrolled in this study have been described previously 14 15 16 17 .…”

An overview of the genetic basis of cardiovascular disease

“…Our group has recently shown that a gene panel with a yield of >60% in a European population has a yield of 18% in South Africans with HCM, highlighting the need to identify genetic causes of CVD in Africans. [21] Similarly, GVs identified in non-SSA populations need to be treated with caution until population screening in local populations has been performed and verified as pathogenic, as it has previously been demonstrated that rare GVs in European populations could represent common GVs in African populations.…”

A novel TNNI3 gene mutation (c.235C>T/ p.Arg79Cys) found in a thirty-eight-year-old women with hypertrophic cardiomyopathy

“…Family HCM often presents an autosomal dominant (AD) pattern of inheritance, which is due to mutation of the genes encoding sarcomeric proteins. Until now, there are approximately 450 point mutations in 13 genes contributing to HCM, among which, beta-myosin heavy chain ( MYH7 ), cardiac troponin I ( TNNI3 ), myosin binding protein C ( MYBPC3 ), cardiac troponin T ( TNNT2 ) are most common [ 1 ]. Families with various mutations of HCM exhibit a variety of phenotypes and prognosis.…”