CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 6, July 2013
AFRICA
233
Discussion
We have identified 14 mutations in 34 of 44 (77 %) SouthAfrican
probands screened; two (14%) of the mutations identified are
novel. The disease-causing mutations of 33 probands were
identified by multi-CE-SSCP (Table 2), which represents a
detection rate of 75%. Additionally, applying direct DNA
sequencing to a smaller cohort resulted in the detection of the
disease-causing mutation in 30 of the 32 probands screened,
which represents a total detection rate of 94%.
These results are comparable to those reported in other
screening studies.
22,24,25
Therefore, in comparison to just screening
for the KCNQ1:p.A341V founder mutation in our cLQTS
probands (which had a detection rate of 52%), the addition
of other genes and the application of direct DNA sequencing
for mutation screening resulted in manifest improvements in
diagnostic efficiency.
Within the founder families, represented by 23 probands, two
probands (8.5 %) were double heterozygotes. One case carried
KCNQ1:p.A341V and KCNH2:p.R328C while the other carried
KCNQ1:p.A341V and KCNE1:p.D91E. This is an important
finding as one of the purposes of genetic screening in cLQTS
probands is the identification of asymptomatic mutation carriers
in family members (cascade screening) in order to clinically
assess the need for prophylaxis.
In theory, half of the mutation carriers within a cLQTS
family may be missed if only one of the mutations in a
compound heterozygote or double heterozygote is identified
through selective screening for only one mutation or the selective
screening of only one of the involved genes. As the clinical
presentation may be sudden death in cLQTS mutation carriers,
this is a serious clinical problem. Our results demonstrate that
the detection of compound and double heterozygotes is also an
important consideration in clinical handling of cLQTS cases in
South Africa.
KCNQ1 mutations
The common South African founder mutation (p.A341V) was
identified in 23 probands.
20,21
p.V254M was first identified in
a large LQT1-kindred
6
and later associated with sudden death
before 40 years of age.
26
This mutation was found to exert a
dominant negative effect on native IKs.
27
Assessment of beta-
blocker therapy was performed on a cLQTS family carrying
p.V254M; treatment was determined to be effective and safe.
28
p.Y315C has been shown to be a dominant negative mutation,
which, while the protein was normally trafficked to the cell
surface, produced no measurable current.
29
This mutation has
been shown to be associated with cisapride-induced QT
prolongation.
30
p.Y315S was first identified in a French LQTS family.
26
Jongbloed
et al
. (1999) identified this mutation as a
de novo
cause of cLQTS, which appeared to be triggered by both physical
and emotional stress.
31
In both cases the mutation was associated
with an onset of symptoms before 10 years of age.
p.L342F was previously reported by Donger
et al
. (1997)
where it was identified in a single case; none of the other family
members carrying the mutation presented with symptoms
of LQTS.
26
However, the proband had experienced onset of
symptoms before the age of 10 years.
p.A341E was identified in the first double heterozygote-
carrying cLQTS family identified in a French cLQTS
cohort,
32
where carriers of both mutations (KCNQ1:p.A341E
and KCNH2:c.2592+1G
>
A) were reported to be severely
symptomatic, with both stress- and rest-induced symptoms
initiating in early childhood. The mutation was found to exert a
dominant negative effect on native IKs.
27
The p.A344V mutation was first identified as a
forme fruste
cause of LQTS.
26
Later, Choi
et al
. (2004) discovered this
mutation in a cohort of patients, which had suffered swimming-
triggered arrhythmias.
33
In addition to shifting the voltage
TABLE 2. DISEASE-CAUSING MUTATIONS IDENTIFIED IN THE SOUTHAFRICAN LQTS PROBANDS
ASWELLASAN INDICATION OFWHICH PLATFORM IDENTIFIED THEVARIANT
Gene/
protein
Mutations
Mutation detection
technique
Frequency
in
in silico
controls Av QTc/additional info References
Coding
substitution
Protein
consequence SSCP sequencing total
KCNQ1/
Kv7.1
c.760G
>
A
p.V254M 1
ns
1
0
500 ms/ICD 4–6, 25–28, 33, 45, 55–58
c.944A
>
G
p.Y315C
0
1
1
0
550 ms
4, 5, 25, 29, 33, 57, 59–62
c.944A
>
C
p.Y315S
1
ns
1
0
512 ms
4, 26, 31, 57
c.1022C
>
A
p.A341E
1
ns
1
0
502 ms/CA at 51 years 4, 5, 27, 32, 45, 57, 59, 63, 64
c.1022C
>
T
p.A341V 23
23
23
0
513 ms/BB 4–6, 20, 21, 25–27, 45, 65–75
c.1024C
>
T
p.L342F
1
1
1
0
527 ms
4, 5, 24, 26, 76, 77
c.1031C
>
T
p.A344V
2
2
3
#
0
557 ms
4, 5, 25, 26, 33, 34, 57, 68
c.1760C
>
T
p.T587M 1
ns
1
0
400 ms
4, 5, 24, 35–37, 59, 78–80
KCNH2/
Kv11.1
c.208C
>
A
p.R100W 1
1
1
0
437 ms
5
c.917-3T
>
C
defective splicing/
protein degradation 0
1
1
0
450 ms
This study
c.982C
>
T*
p.R328C*
0
1
1
0
654 ms*
4, 5, 25, 30, 39, 40, 47, 48, 81–83
c.1714G
>
A
p.G572S
1
1
1
0
402 ms/BB 4, 5, 24, 25, 39–44
c.1882C
>
G
p.F627L
1
ns
1
0
462 ms
4, 45, 46
KCNE1/
MinK c.273C
>
A*
p.D91E*
1
1
1
0 (EA);
0.0002 (AA)
533 ms*
This study
*Variants that co-occur with Kv7.1:p.A341V;
#
One of the probands in which p.A344V had been identified previously by SSCP was not available for
sequencing. ns: not screened by sequencing; EA: 8 600 European-Americans screened by exome sequencing; AA: 4 406 African-Americans screened by
exome sequencing; ICD: implantable cardioverter defibrillator; CA: cardiac arrest. BB: beta-blockers.
