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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 3, May/June 2016
152
AFRICA
Clinical features, spectrum of causal genetic mutations
and outcome of hypertrophic cardiomyopathy in South
Africans
Ntobeko AB Ntusi, Gasnat Shaboodien, Motasim Badri, Freedom Gumedze, Bongani M Mayosi
Abstract
Background:
Little is known about the clinical characteristics,
spectrum of causal genetic mutations and outcome of hyper-
trophic 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, electrocar-
diographic 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
β
-myosin heavy chain
(
MYH
7), cardiac troponin T2 (
TNNT2
), cardiac troponin I
(
TNNI3
), regulatory light chain of myosin (
MYL2
), essen-
tial 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 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 muta-
tions 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 mortal-
ity 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.
Keywords:
hypertrophic cardiomyopathy, genetics, clinical char-
acteristics, outcome, South Africa
Submitted 2/5/14, accepted 15/9/15
Cardiovasc J Afr
2016;
27
: 152–158
www.cvja.co.zaDOI: 10.5830/CVJA-2015-075
Hypertrophic cardiomyopathy (HCM) is defined by the presence
of myocardial hypertrophy in the absence of haemodynamic
stresses sufficient to account for the degree of hypertrophy (e.g.
arterial hypertension and aortic stenosis), and without other
secondary causes of cardiac hypertrophy, such as amyloidosis
and glycogen storage disease.
1
HCM was historically thought to be rare among Africans.
2
This impression was reinforced by a study that found HCM to
occur in 0.2% of 6 680 unselected echocardiograms performed in
Tanzania.
3
However, recent echocardiographic studies from the
continent have dispelled thatmyth.
4
For example, inGhana, HCM
has been reported to be the third commonest cardiomyopathy
after dilated cardiomyopathy (DCM) and endomyocardial
fibrosis (EMF).
5
Similarly, in Ethiopia, HCM accounts for
34% of all cardiomyopathies diagnosed on echocardiography.
6
However, there is a dearth of information on the clinical features,
genetics and outcome of HCM from the African continent,
with a few publications reporting on HCM-causing mutations
in South Africans of northern European descent and mixed
ancestry.
7-10
To the best of our knowledge, there are no data on
the genetics of HCM in black Africans.
HCM is a diverse disease with variable phenotypic expression;
a substantial proportion of patients live a normal life with
minimal risk of sudden cardiac death.
11
However, some patients
with or without symptoms may die suddenly, even without
having clinical features of severe left ventricular hypertrophy
(LVH).
9
The pattern of LVH in HCM is variable and associated with
differences in morbidity and mortality. For instance, apical
HCM in the Japanese and North American populations is
Cardiovascular Genetics Laboratory, Hatter Institute for
Cardiovascular Research in Africa and The Cardiac Clinic,
Department of Medicine, Groote Schuur Hospital and
University of Cape Town, Cape Town, South Africa
Ntobeko AB Ntusi, MB ChB, FCP (SA), DPhil, MD, ntobeko.ntusi@
gmail.comGasnat Shaboodien, PhD
Motasim Badri, PhD
Bongani M Mayosi, MB ChB, FCP (SA), DPhil
King Saud Bin Abdulaziz University for Medical Sciences,
Riyadh, Kingdom of Saudi Arabia
Motasim Badri, PhD
Department of Statistical Sciences, University of Cape
Town, Cape Town, South Africa
Freedom Gumedze, PhD