CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 6, July 2013
AFRICA
231
Long QT syndrome in South Africa: the results of
comprehensive genetic screening
PAULA L HEDLEY, GLENDA A DURRHEIM, FIRZANA HENDRICKS, ALTHEA GOOSEN, CATHRINE
JESPERSGAARD, BIRGITTE STØVRING, TAM T PHAM, MICHAEL CHRISTIANSEN, PAUL A BRINK,
VALERIE A CORFIELD
Abstract
Congenital long QT syndrome (cLQTS) is a genetic disor-
der predisposing to ventricular arrhythmia, syncope and
sudden death. Over 700 different cLQTS-causing muta-
tions in 13 genes are known. The genetic spectrum of LQTS
in 44 South African cLQTS patients (23 known to carry
the South African founder mutation p.A341V in
KCNQ1
)
was established by screening for mutations in the coding
regions of
KCNQ1, KCNH2, KCNE1, KCNE2
and
SCN5A,
the
most frequently implicated cLQTS-causing genes (five-gene
screening). Fourteen disease-causing mutations were identi-
fied, eight (including the founder mutation) in
KCNQ1
, five
in
KCNH2
and one in
KCNE1
. Two mutations were novel.
Two double heterozygotes were found among the 23 fami-
lies (8.5%) carrying the founder mutation. In conclusion,
cLQTS in South Africa reflects both a strong founder effect
and a genetic spectrum similar to that seen in other popula-
tions. Consequently, five-gene screening should be offered as
a standard screening option, as is the case internationally.
This will disclose compound and double heterozygotes. Five-
gene screening will most likely be even more informative in
other South African sub-populations with a greater genetic
diversity.
Keywords:
LQTS, mutation, ion-channels, sudden death,
arrhythmia
Submitted 4/3/13, accepted 24/5/13
Cardiovasc J Afr
2013;
24
: 231–237
DOI: 10.5830/CVJA-2013-032
The congenital long QT syndrome (cLQTS)
1
is an inherited
disorder characterised by prolongation of the QT interval on
a surface electrocardiogram (ECG) and an increased risk for
life-threatening ventricular arrhythmias,
2
particularly ventricular
tachycardia of the torsades de pointes type. cLQTS provides
the archetypical monogenic disorder for studying the genetic
basis of inherited arrhythmia syndromes in that it is relatively
common (prevalence of 1:2 500 to 1:5 000),
3
and more than
700 disease-causing mutations have been identified in 13 genes
encoding different cardiac ion channels or membrane adaptors.
4,5
The genetic and allelic heterogeneity results in subtly different
clinical phenotypes.
6
Several clinical syndromes have been described: Romano-
Ward syndrome (RWS), an autosomal dominant form of cLQTS,
which presents clinically with a pure cardiac phenotype; Jervell
and Lange-Nielsen syndrome (JLNS), an autosomal recessive
form of LQTS which is associated with congenital deafness;
2
Andersen-Tawil syndrome (ATS), which is an autosomal
dominant multisystem disorder where cLQTS is variably present;
and Timothy syndrome (TS), which is characterised by severe
cLQTS as well as cardiac and somatic malformations.
cLQTS is associated with loss-of-function mutations in
genes encoding repolarising K
+
ion channels, their subunits
and certain interacting proteins, i.e.
KCNQ1
encoding Kv7.1
(LQT1),
6
KCNH2
encoding Kv11.1 (LQT2),
7
ANK2
encoding
Ankyrin B (LQT4),
8
KCNE1
encoding MinK (LQT5),
9,10
KCNE2
encoding MiRP1 (LQT6),
11
KCNJ2
encoding Kir2.1 (LQT7),
12
CAV3
encoding M-Caveolin (LQT9),
13
SCN4B
encoding Nav
β
3
(LQT10),
14
AKAP9
encodingYotiao (LQT11),
15
SNTA1
encoding
α
1-Sytophin (LQT12)
16
and
KCNJ5
encoding Kir3.4 (LQT13).
17
Furthermore, gain-of-function mutations in genes encoding
depolarising Na
+
and Ca
2+
ion channels have also been associated
with LQTS, i.e.
SCN5A
(LQT3)
18
and
CACNA1C
(LQT8).
19
The ion channel defects result in either decreased K
+
efflux
or increased Na
+
or Ca
2+
influx over the cardiomyocyte plasma
membrane, leading to reduced repolarisation and increased
frequency of after-depolarisations (ADs) and prolonged
refractory period. The latter predisposes to re-entrant
ventricular arrhythmia.
4
Adrenergic stimulation, which increases
the frequency of ADs, may precipitate fatal arrhythmia in
asymptomatic mutation carriers.
1,4
Drugs, e.g. amiodarone,
cisapride, sotalol and haloperidol, which reduce the repolarisation
reserve, may cause drug-related LQTS (dLQTS) or, likewise,
precipitate arrhythmia in mutation carriers.
1,4
Previously, de Jager
et al
. and Brink
et al
. reported on
the Kv7.1 (encoded by
KCNQ1
) founder mutation, p.A341V,
identified in 23 Afrikaner families.
20,21
Little is known of the
occurrence of other cLQTS-associated mutations in SouthAfrica.
In order to describe the spectrum of mutations causing
cLQTS in South Africa, we screened 44 apparently unrelated
US/MRC Centre for Molecular and Cellular Biology,
Department of Biomedical Sciences, Faculty of Medicine and
Health Sciences, University of Stellenbosch, South Africa
PAULA L HEDLEY, MSc
GLENDA A DURRHEIM, MSc
FIRZANA HENDRICKS, MB ChB
VALERIE A CORFIELD, PhD,
Department of Clinical Biochemistry, Immunology and
Genetics, Statens Serum Institut, Denmark
PAULA L HEDLEY, MSc
CATHRINE JESPERSGAARD, PhD
BIRGITTE STØVRING, PhD
TAM T PHAM, MSc
MICHAEL CHRISTIANSEN, MB ChB
Department of Internal Medicine, Faculty of Medicine and
Health Sciences, University of Stellenbosch, South Africa
ALTHEA GOOSEN, RN
PAUL A BRINK, MD, PhD
