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

Background: Little 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. Methods: Information 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 myosin-binding protein C (MYBPC3), cardiac beta-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), alpha-actin (ACTC1), cysteine and glycine-rich protein 3 (CSRP3), AMP-activated protein kinase (PRKAG2), alpha-galactosidase (GLA), four-and-a-half LIM domains 1 (FHL1), lamin A/C (LMNA) and lysosome-associated membrane protein 2 (LAMP2). Survival and its predictors were analysed using the Kaplan-Meier and Cox proportional hazards regression methods, respectively. Results: Forty-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). Conclusions: Comprehensive 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.