CLINICAL REPORT
Autosomal recessive long QT syndrome, type 1 in eight
families from Saudi Arabia
Amnah Y. Bdier1,2, Saleh Al-Ghamdi3, Prashant K. Verma2,4, Khalid Dagriri5, Bandar Alshehri2,
Omamah A. Jiman3, Sherif E. Ahmed1,2,6, Arthur A. M. Wilde7, Zahurul A. Bhuiyan8,a
&
Jumana Y. Al-Aama2,4,a
1
Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
Princess Al Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
3
Department of Genetic Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
4
Department of Cardiology, NGH, Riyadh, Saudi Arabia
5
Department of Pediatric Cardiology, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia
6
Department of Genetics, Faculty of Agriculture, Ain shams University, Cairo, Egypt
7
Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
8
Laboratoire de G
enetique Moleculaire, Service de medecine g
en
etique, CHUV, Lausanne, Switzerland
2
Keywords
Arrhythmia, autosomal recessive, long QT
syndrome, Saudi Arabia
Correspondence
Zahurul A. Bhuiyan, Laboratoire de
G
en
etique Mol
eculaire, Service de medecine
g
en
etique, CHUV, Rue du Bugnon 46,
Lausanne 1011, Switzerland.
Tel.: +41 213143370; Fax: +41 213143385;
E-mail: Z.A.Bhuiyan@chuv.ch
and
Jumana Y. Al-Aama, Princess Al Jawhara
Albrahim Center of Excellence in Research of
Hereditary Disorders, King Abdulaziz
University, Jeddah, Saudi Arabia.
Tel.: +966 50 777 3834;
Fax: +966 12 2335553;
E-mail: jalama@kau.edu.sa
Funding Information
King Abdulaziz City for Science and
Technology (Grant/Award Number: 10-BIO1075-03).
Received: 27 March 2017; Revised: 18 May
2017; Accepted: 22 May 2017
Molecular Genetics & Genomic Medicine
2017; 5(5): 592–601
doi: 10.1002/mgg3.305
Abstract
Background
One of the most common primary cardiac arrhythmia syndromes is autosomal
dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono-allelic
mutations in the KCNQ1 gene. Bi-allelic mutations in the KCNQ1 gene are
causal to Jervell and Lange-Nielsen syndrome (JLNS), characterized by severe
and early-onset arrhythmias with prolonged QTc interval on surface ECG and
sensorineural deafness. Occasionally, bi-allelic mutations in KCNQ1 are also
found in patients without any deafness, referred to as autosomal recessive long
QT syndrome, type 1 (AR LQT1).
Methods
We used Sanger sequencing to detect the pathogenic mutations in KCNQ1 gene
in eight families from Saudi Arabia with autosomal recessive LQT1.
Results
We have detected pathogenic mutations in all eight families, two of the mutations are founder mutations, which are c.387-5T>A and p.Val172Met/
p.Arg293Cys (in cis). QTc and cardiac phenotype was found to be pronounced
in all the probands comparable to the cardiac phenotype in JLNS patients.
Heterozygous carriers for these mutations did not exhibit any clinical phenotype, but a significant number of them have sinus bradycardia.
Conclusion
To the best of our knowledge, this is the first description of a large series of
patients with familial autosomal recessive LQT, type 1. These mutations could
be used for targeted screening in cardiac arrhythmia patients in Saudi Arabia
and in people of Arabic ancestry.
a
ZAB and JYA are shared last and
corresponding authors.
592
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This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
A. Y. Bdier et al.
What’s new?
• Largest comprehensive phenotype–genotype study on
eight families that have homozygous mutations in the
KCNQ1 gene without having any auditory problem in
the proband and so called Autosomal Recessive Long
QT Syndrome, Type 1 (AR LQT1).
• Patients in five of the eight families carry the same
mutation (c.387-5T>A), which is considered founder
mutations causal to AR LQT1. Second founder mutation is p.Val172Met/p.Arg293Cys (in cis)
• High rate of consanguinity could bring two identical
autosomal dominant LQTS causal mutations together,
resulting in AR LQT1.
• We also observed that heterozygous carriers for these
mutations do not exhibit any clinical phenotype, but a
significant number of them have sinus bradycardia,
which we postulate could lead to the detection of a
long QT syndrome family.
Introduction
Congenital LQTS is an inherited cardiac repolarization disorder characterized by prolongation of corrected QT interval on the ECG and some low cardiac output events like
syncope, seizures, and sudden cardiac death (SCD) due to
ventricular tachyarrhythmia (Mizusawa et al. 2014). The
most common form of LQTS is LQT1, with a prevalence of
1 in 2000 people worldwide (Mizusawa et al. 2014), which
is inherited as an autosomal dominant pattern, while Jervell
and Lange-Nielsen syndrome (JLNS) is a rare condition
observed in less than one per four million individuals
(Mizusawa et al. 2014), which is an autosomal recessive
disease, characterized by prolonged QTc, cardiac arrhythmias, and congenital deafness (Mizusawa et al. 2014). The
15 different genes identified so far (Mizusawa et al. 2014)
associated with LQTS, encode for cardiac ion channels and
its chaperones and are involved in the cardiac depolarization and repolarization. Among them most common are
LQT1, LQT2, and LQT3, caused by mutations in KCNQ1,
KCNH2, and SCN5A genes, respectively (Splawski et al.
2000; Westenskow et al. 2004; Mizusawa et al. 2014).
Mutations in these three genes are found in more than 90%
of genotype-positive patients (Splawski et al. 2000; Westenskow et al. 2004; Mizusawa et al. 2014). Among all the
reported mutations, missense mutations constitute the
major type followed by frameshift mutations, in-frame
deletions, nonsense and splice site mutations (Splawski
et al. 2000; Westenskow et al. 2004; Mizusawa et al. 2014).
KCNQ1 gene encodes for the Kv7.1 subunit (potassium
channel) of the slowly activating delayed rectifier outward
K+ current (IKs) channel, found in the heart and inner
Autosomal Recessive Long QT Syndrome, Type 1
ear (Bhuiyan and Wilde 2013). Heterozygous nonsense or
truncating mutations in KCNQ1 lead to loss of function
of the mutant allele (haploinsufficiency), which usually
could not exert any dominant negative effect on the
opposite normal allele (Bhuiyan and Wilde 2013). Hence,
mono-allelic KCNQ1 nonsense or truncating mutation
carriers are often asymptomatic (Bhuiyan and Wilde
2013). But, heterozygous missense mutations with its
dominant negative effect on the opposite normal allele
confer pathogenicity and lead to autosomal dominant
LQT1 and its sequelae (Bhuiyan and Wilde 2013).
Homozygous or compound heterozygous mutations that
lead to complete loss of function of the IKs protein are
causal to the recessive form of the disease, Jervell and
Lange-Nielsen syndrome (JLNS), with more severe cardiac
phenotype than the dominant form of LQT1 and with
the additional feature of Sensorineural Hearing Loss
(SNHL) (Bhuiyan and Wilde 2013).
Occasionally, with homozygous or compound
heterozygous mutations in the KCNQ1 gene, there could
still remain some IKs protein residues (Bhuiyan and
Wilde 2013). These individuals present cardiac manifestations only, without any hearing defect; this is regarded
as autosomal recessive LQTS type 1 (AR LQT1), which
was first reported by Priori et al. in 1998 (5). Since then,
few other studies have been published describing this
type of AR LQT1 (Priori et al. 1998; Larsen et al. 1999;
Ning et al. 2003; Westenskow et al. 2004; Novotny et al.
2006; Bhuiyan et al. 2008; Jackson et al. 2014; Vyas et al.
2016).
The first report on AR LQT1 in Saudi Arabia was published in 2008 (Bhuiyan et al. 2008). Bhuiyan et al. (2008)
described a novel homozygous founder mutation in the
splice site at intron-1-exon-2 of the KCNQ1 gene (c.3875T>A) which caused only severe arrhythmias (without any
auditory phenotype) in three children from two families
(Bhuiyan et al. 2008). Most cases of AR LQT1 reported so
far have been sporadic affecting a single individual. In this
prospective study, we present our data from eight families
in Saudi Arabia that have homozygous mutations in the
KCNQ1 gene without having any auditory problem in the
proband and in their siblings. To the best of our knowledge, this is the first description of a large series of patients
with familial AR LQT1.
Methodology
Clinical analysis
Eight families with a family history of syncope, seizures,
and sudden cardiac death were diagnosed by the cardiologists and recruited for genetic study. Clinical investigation
was performed in the eight probands and their families
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Autosomal Recessive Long QT Syndrome, Type 1
A. Y. Bdier et al.
by taking full family history, ECG, and construction of
family pedigrees. Families involved in this study are not
related, all originate from different regions in Saudi Arabia. All patients with homozygous mutations underwent
hearing tests, resting ECG was also performed. ECG was
also performed in heterozygous mutation carriers. Hearing test was not performed in heterozygous mutation carriers if there was no indication for any hearing defect.
Mutation analysis
Molecular genetic investigation was done at Princess Al
jawhara Center of Excellence in Research of Hereditary
Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. Blood samples were collected and the
DNA was isolated from peripheral blood leukocytes using
DNA blood mini kit (QIAmp, Qiagen, Inc., Hilden, Germany) following the manufacturer’s instructions. All 16
exons of the KCNQ1 genes (RefSeq: NM_000218, UniProt
P51787, OMIM 607542, LRG_287) were amplified from
genomic DNA by primers that cover all exons and exon
intron boundaries, the primers were designed using webbased primer design software, Primer3Plus http://www.b
ioinformatics.nl/cgi-bin/primer3plus/primer3plus.cgi/.
PCR products were purified using QIAquick PCR
purification kit then bidirectionally sequenced using a Big
Dye Terminator v3.1Cycle Sequencing Kit on an ABI
3500 sequencer (Thermo Fisher Scientific Inc, Applied
Biosytems, Foster City, CA, USA). Sequence variants were
analyzed via BioEdit sequence alignment editor version
6.0.7 (http://www.mbio.ncsu.edu/bioedit/bioedit.html).
Results
Family A
The proband (II: 4 in Fig. 1) was a 3-year-old boy who
was suspected to have epilepsy after he experienced an
episode of syncope while swimming. After his neurological evaluation was found to be normal, he was diagnosed
as LQTS with QTc = 557 ms (Table 1). His syncopal
attacks never recurred after he was started on Atelonol
12.5 mg/day. He had a brother and sister (II:2 and 3 in
Fig. 1) who died suddenly (at the age of 10 years while
diving and 5 years while at the playground, respectively).
The sister had a history of loss of consciousness and was
diagnosed with LQTS but not treated. All the children
had normal hearing tests. The parents (I:1 and 2 in
Fig. 1) were consanguineous, asymptomatic, and had normal ECGs. The proband (II:4 in Fig. 1 and Table 1) was
found to be homozygous for the mutation in intron 1 of
KCNQ1 gene at 5-base upstream from the first nucleotide
of exon-2 (c.387-5 T>A; NCBI Ref. NM_000218) and had
been reported as rs794728549.
Moreover, the analysis showed that his parents (I:1 and
I:2 in Fig. 1 and Table 1) and a living brother (II:1 in
Fig. 1 and Table 1) were heterozygous for the same mutation. Detailed clinical phenotype and in vitro electrophysiology analysis data on this family was published
previously (Bhuiyan et al. 2008).
Family B
The proband (II: 5 in Fig. 1) was a 16-year-old boy who
developed generalized seizures at the age of 1 year, lasting
1–2 min with cyanosis of the lips. The attacks were triggered by physical activity and uncontrolled by anti-epileptics. At the age of 4 years, he was reevaluated and
diagnosed with LQTS with prolonged QT interval. His
seizure attacks stopped after starting propranolol treatment. At the age of 16, he was on 20 mg propranolol
three times per day and playing sports without problems.
His ECG showed prolonged QTc of 529 ms (Table 1).
His hearing tests were normal. There is a family history
of seizures in an older brother who died at the age of
2 years (II: 4 in Fig. 1), who had no hearing abnormality.
His parents and other siblings were asymptomatic (I1, 2
and II: 1,2 and 3 in Fig. 1). Genetic investigation detected
homozygous mutation c.387-5T>A in the KCNQ1 gene in
II: 5 (Fig. 1 and Table 1). This was found heterozygously
in his father and one brother (I:1 and II: 3 in Fig. 1 and
Table 1). The mother’s DNA was not available for genetic
testing. Detailed clinical phenotype and functional data
on this family was published previously (Bhuiyan et al.
2008).
Family C
The proband (II:1 in Fig. 1) was a 16-year-old boy who
had syncope at the age of 10 years, referred to cardiology
Figure 1. Pedigrees structure of eight families with AR LQT1 patients. Proband in each family is shown with an arrow mark. Circles are denoted
for female and squares are denoted for male. Black-filled circles and squares in all pedigrees are confirmed AR LQT1 patients. Half-filled circles or
squares denote heterozygotes for the familial mutation. Consanguineous marriages are indicated by =. Deceased individuals with the disease are
shown with a diagonal line. Baseline ECG from the probands and all homozygote family members are shown below or beside each family tree.
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A. Y. Bdier et al.
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Autosomal Recessive Long QT Syndrome, Type 1
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Autosomal Recessive Long QT Syndrome, Type 1
A. Y. Bdier et al.
clinic and diagnosed with LQTS. He was diagnosed previously to have seizure disorder at the age of 8 months. He
is on propranolol treatment. His 9-year-old brother (II:2
in Fig. 1) only had dizziness and is on propranolol. An 8year-old sister (II:3 in Fig. 1) is asymptomatic, her heart
rate was 79 beats/min, she was also prescribed Inderal. All
three siblings had sinus rhythm and prolonged QTc
(500 ms, 459 ms, 498 ms, respectively) (Table 1). Their
hearing tests were normal. Their parents (I:1 and I:2 in
Fig. 1) were both asymptomatic with normal ECGs and
no hearing defect. Genetic testing showed the three
children (II: 1, 2, and 3 in Fig. 1 and Table 1) hosting
homozygous mutations c.387-5T>A in the exon-2/
intron-1 junction of the KCNQ1 gene. Both parents were
heterozygous (I:1 and I:2 in Fig. 1 and Table 1) for the
same mutation.
Family D
The proband (II: 2 in Fig. 1) was a 9-year-old girl who
had a single 10-min episode of cardiac arrest that
responded to CPR. She was diagnosed with LQT1 and
ICD was advised but the family refused. She is on propranolol 20 mg TDS. She has a strong family history of sudden death (four members), Her ECG showed sinus
rhythm (80 beats/min) and marked QT prolongation
(537 ms) (Table 1). ECG from the father, mother, and
one brother (I :1,2 and II:1 in Fig. 1) showed bradycardia
(46, 52, 47 beats/min, respectively). Another brother (II:4
in Fig. 1) had prolonged QTc intervals (474 ms)
(Table 1). All the children including the proband had
normal hearing tests. The proband (II:2 in Fig. 1 and
Table 1) was found to have homozygous mutation c.3875T>A in the exon-2/intron-1 junction of the KCNQ1
gene. Three family members (I:1, 2 and II:1, 4 in Fig. 1
and Table 1) were heterozygous carriers for the same
mutation.
Family E
The proband (II: 1 in Fig. 1) was a 1-year-old girl who
had bradycardia since birth and congenital heart defect
(venticular septal defect which closed spontaneously). The
ECG revealed a prolonged QTc interval. She does not
have SNHL. There is no family history of sudden death,
arrhythmia, or SNHL. She is currently on propranolol
1 mg/kg. Her latest ECG showed sinus rhythm (115
beats/min) and marked QTc prolongation (531 msec)
(Table 1). Her parents had normal ECGs (Table 1). The
proband (II: 1 in Fig. 1 and Table 1) was found to have a
homozygous mutation c.387-5T>A in the KCNQ1 gene.
Her parents (I:1 and I:2 in Fig. 1 and Table 1) were
heterozygous for the same mutation.
596
Family F
The proband (II: 4 in Fig. 1) was a 12-year-old boy who
had palpitations and chest pain starting at the age of
3 years related to fear and auditory stimuli. He had recurrent loss of consciousness 10–15 min per episode,
approximately three times per day. He was initially diagnosed as having epileptic seizures and prescribed anti-epileptic medication without any improvement. Recently, he
was diagnosed with LQTS with a QTc interval of 534 ms.
He was started on propranolol and the symptoms
improved drastically. His parents are asymptomatic. He
has two asymptomatic brothers, 16 years old and
8 months old (II: 3 and 5 in Fig. 1). The elder brother’s
QTc interval was 444 ms (upper limit of normal). The
younger brother had prolonged QTc interval (496 ms)
(Table 1). All the children including the proband had
normal hearing tests. There is a history of seizures in a
paternal half-sister and sudden death in a 24-year-old
paternal half-brother (II: 2 in Fig. 1). This brother has a
child who is now 6 years old (III:1 in Fig. 1). There is a
family history of sudden death and suspected LQTS in
extended members of the proband’s father’s family. Also,
the proband’s maternal aunt has deafness. Genetic testing
showed homozygous mutations c.535G>A (p.Gly179Ser)
in the proband and his two siblings (II: 3, 4 and 5 in
Fig. 1 and Table 1). Their father and the 6-year-old
nephew (I:2 and III:1 in Fig. 1 and Table 1) were found
heterozygous carriers for the same mutation. Mother
declined to do the genetic testing.
Family G
The proband (II: 1 in Fig. 1) was a 7-year-old boy who
had one episode of syncope precipitated by fear. His hearing tests were normal. There is a family history of sudden
deaths in two siblings, first one at the age of 4 years with
the diagnosis of seizure disorder, while the other one died
at the age of 1 year after a short febrile illness. The proband’s ECG showed sinus bradycardia (57 beats/min) and
prolonged QTc (580 ms) (Table 1). The ECGs of the parents were also abnormal showing prolonged QTc
(Table 1). The proband (II: 1 in Fig. 1 and Table 1) was
found to have homozygous mutations c.1031C>T
(p.Ala344Val) in the KCNQ1 gene. His parents (I:1 and
I:2 in Fig. 1 and in Table 1) were heterozygous for the
same mutation.
Family H
The proband (II: 1 in Fig. 1) is a 12-year-old boy who
experienced one syncopal attack at the age of 11 years.
The ECG showed prolonged QTc intervals and was
ª 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Family
numbers
ID, age(yrs),
gender
A
Age at first
presentations (yrs)
QTc (ms)
Genotype
II:4, 3, m
Syncope
557
II:1, m
n.s
430
I:1, m
n.s
459
I:2, f
n.s
431
Seizure attacks
n.s
n.s
529
n.a
n.a
c.[387-5 T>A];
p. [?]; [?]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
c.[387-5 T>A];
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
c.[387-5 T>A];
p. [?]; [?]
c.[387-5 T>A];
p. [?]; [?]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
p. [?]; [?]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
p. [?]; [=]
c.[387-5 T>A];
p. [?]; [=]
B
II:5, 16, m
II:3, m
I:1, m
C
II:1, 16, m
II:2, 9, m
Dizziness
500
459
II:3, 8, f
n.s
498
I:1, 44, m
n.s
444
I:2, 44, f
n.s
467
II:2,9, f
537
II:1, 15, m
Episode of cardiac
arrest
Bradycardia
II:4, 2, f
n.s
474
I:1, m
Bradycardia
404
I :2, f
Bradycardia
457
D
1
435
Medication
Response to medication
[387-5 T>A]
Atenolol (12.5 mg bd)
Well response
[=]
n.m
[=]
n.m
[=]
n.m
[387-5 T>A] p. [?]; [?]
[=] p. [?]; [=]
[=]
Propranolol (20 mg tid)
n.m
n.m
[387-5 T>A] p. [?]; [ ?]
[387-5 T>A]
Inderal
[387-5 T>A]
Inderal
[=]
n.m
[=]
n.m
[387-5 T>A]
Propranolol (20 mg tds),
[=]
n.m
[=]
n.m
[=]
n.m
[=]
n.m
Well response
(Continued)
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Autosomal Recessive Long QT Syndrome, Type 1
Symptoms
A. Y. Bdier et al.
ª 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Table 1. Genotype status of all the genotype-positive patients from the eight families with AR LQT1 patients. Clinical symptoms (if any), QTc interval, pharmacological intervention (if any), and
other relevant parameters of the AR LQT1 patients as well as the heterozygote family members are also mentioned.
Family
numbers
ID, age(yrs),
gender
Age at first
presentations (yrs)
Symptoms
QTc (ms)
Genotype
Medication
Response to medication
E
II:1, 1, f
Since birth
Bradycardia
531
Propranolol (1 mg/kg)
Well response
I:1, 32, m
n.s
399
I:2, 25, f
Bradycardia
418
534
II:3, 16, m
Palpitation, seizures,
chest pain, loss of
consciousness
n.s
c.[387-5 T>A]; [387-5 T>A]
p. [?]; [?]
c.[387-5 T>A]; [=]
p. [?]; [=]
c.[387-5 T>A]; [=]
p. [?]; [=]
c.[535G>A]; [535G>A]
p.[Gly179Ser]; [Gly179Ser]
B. blocker (2 mg/kg/bd)
II:5, 8 mos, m
n.s
496
III:1, 6, m
n.s
448
I:2, 60, m
n.s
467
II:1, 7, m
580
I:1,, m
Syncope,
bradycardia
n.s
I:2,, f
n.s
478
Syncope
485
I:1,44, m
n.s
417
I:2, 42, f
n.s
415
c.[535G>A]; [535G>A]
p.[Gly179Ser]; [Gly179Ser]
c.[535G>A]; [535G>A]
p.[Gly179Ser]; [Gly179Ser]
c.[535G>A]; [=]
p.[Gly179Ser]; [=]
c.[535G>A]; [=]
p.[Gly179Ser]; [=]
c.[1031 C>T]; [1031 C>T]
p.[A344V]; [A344V]
c.[1031 C>T]; [=]
p.[A344V]; [=]
c.[1031 C>T]; [=]
p.[A344V]; [=]
c.[514G>A]; [514G>A]
p. [V172M];[ V172M] and
c.[877C>T]; [877C>T]
p. [R293C];[R293C]
c.[514G>A; 877C>T]; [=]
p.[V172M; R293C];[ =]
c.[514G>A; 877C>T]; [=]
p. [V172M; R293C];[ =]
F
H
II:1,12, m
3
11
n.a, not available; n.s, no symptoms; n.m, no medication.
444
443
n.m
B. blocker (2 mg/kg/bd)
Well response
B. blocker (2 mg/kg/bd)
ICD implanted
n.m
n.m
n.m
Propranolol (10 mg tid)
n.m
n.m
A. Y. Bdier et al.
ª 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
G
II:4, 12, m
n.m
Autosomal Recessive Long QT Syndrome, Type 1
598
Table 1. Continued.
A. Y. Bdier et al.
Autosomal Recessive Long QT Syndrome, Type 1
started on propranolol. Since then there had been no
events of syncope, loss of consciousness, or seizures. His
hearing tests were normal. There is no family history of
LQTS. The proband is currently on propranolol 10 mg
TDS (39 per day). His ECG showed sinus rhythm (67
beats/min) and marked QTc prolongation (485 msec)
(Table 1). The proband (II: 1 in Fig. 1 and Table 1) has
two homozygous mutations c.514G>A (p.Val172Met) and
c.877C>T (p.Arg293Cys) in the KCNQ1 gene, both mutations are located in cis. His parents (I:1 and I:2 in Fig. 1
and in Table 1) were found to be heterozygous for both
mutations in cis, c.[514G>A;877C>T], p.[Val172Met;
Arg293Cys], that is, they are not compound heterozygous
mutations.
Bradycardia in the heterozygous mutation
carriers
Bradycardia was occasionally reported in patients with
clinically symptomatic autosomal dominant LQT1
patients with heterozygous KCNQ1 mutations (Moss
et al. 1991; Lupoglazoff et al. 2004). We tried to assess
the heart rate in nonsymptomatic, heterozygous, mild,
KCNQ1 mutation carriers. As patients with homozygous
mutations were having b-blockers, we evaluated the family members having a heterozygous mutation in the
KCNQ1 gene. In total, we have analyzed the heart rate in
16 heterozygous KCNQ1 mutation carriers; sinus bradycardia (≤60 beats/min) was observed in 50% of the
heterozygous carriers (n = 8), matching against age-specific control values. This has been shown in Table 2.
Table 2. Basal heart rate of the heterozygous KCNQ1 mutation carriers (without b-blocker).
Family id
Patient’s name
Mutation
Basal heart rate
Family A
Father of proband
Mother of proband
Mother of proband
Father of proband
Mother of proband
Father of proband
Mother of proband
16-year-old brother
of proband
Father of Proband
Mother of proband
Father of proband
Son of proband
Father of proband
Mother of proband
Father of proband
Mother of proband
c.387-5T>A
c.387-5T>A
c.387-5T>A
c.387-5T>A
c.387-5T>A
c.387-5T>A
c.387-5T>A
c.387-5T>A
53
78
55
75
79
58
65
60
beats/min
beats/min
beats/min
beats/min
beats/min
beats/min
beats/min
beats/min
c.387-5T>A
c.387-5T>A
p.Gly179Ser
p.Gly179Ser
p.Ala344Val
p.Ala344Val
p.Arg293Cys
p.Arg293Cys
72
52
79
60
65
54
60
83
beats/min
beats/min
beats/min
beats/min
beats/min
beats/min
beats/min
beats/min
Family B
Family C
Family D
Family E
Family F
Family G
Family H
Discussion
In this study, we performed comprehensive clinical and
molecular screening of the KCNQ1 gene in a series of
patients from eight families with AR LQT1 in Saudi Arabia. Mutation c.387-5T>A was detected in five families
making it likely the most common LQT1 causal founder
mutation in Saudi Arabia. Previously, two of these families
(A and B) were reported by Bhuiyan et al. (10). Additional
AR LQT1 causal mutations detected are: p.Gly179Ser,
p.Ala344Val, p.Val172Met, p.Arg293Cys found in three
more families. p.Val172Met and p.Arg293Cys are situated
in cis. p.Gly179Ser mutation has been previously reported
in the compound heterozygous situation with p.Gln530X
in autosomal recessive LQT1 (Giudicessi and Ackerman
2013). The p.Ala344Val mutation has been described as a
mild/forme fruste LQT1 mutation (Donger et al. 1997;
Siebrands et al. 2006), it was also described in connection
to increased local anesthetic sensitivity (Siebrands et al.
2006; Hedley et al. 2013). Later, Choi et al. (2004) discovered this mutation in a cohort of patients, who had suffered swimming-triggered arrhythmias. p.Val172Met and
p.Arg293Cys, located in cis, has first been described in
Qatari population by exome sequencing (Yavarna et al.
2015). This is very likely another founder mutation in the
Arab region, which deserves further population studies
(Yavarna et al. 2015).
None of the probands with homozygous mutations in
our study have deafness, but, their cardiac phenotypes are
severer and the QTc is longer than patients with the autosomal dominant long QT syndrome (Priori et al. 1998;
Larsen et al. 1999; Ning et al. 2003; Westenskow et al.
2004; Novotny et al. 2006; Bhuiyan et al. 2008; Jackson
et al. 2014; Vyas et al. 2016). This is in agreement with
the hypothesis drawn by Bhuiyan et al. (2008); Bhuiyan
and Wilde 2013), and Priori et al. (Priori et al. 1998),
which explains that KCNQ1 mutations causal to recessive
LQT1 are usually mild and they could still have some
residual IKs in the patient’s heart and ear. On the other
hand, JLNS causal KCNQ1 mutations are severe and IKs
is completely absent in JLNS patients (Priori et al. 1998;
Bhuiyan et al. 2008). This residual minor quantity of IKs
is sufficient to preserve the hearing function in recessive
LQT1 patients (Bhuiyan et al. 2008).
All the 16 heterozygous mutation carriers were asymptomatic. Their QTcs were normal to only slightly prolonged. However, eight of these mutation carriers had
sinus bradycardia. This observation of sinus bradycardia
is known to occur in heterozygous carriers of other
arrhythmia-related genes (SCN5A, HCN4 etc) (Milanesi
et al. 2006; Selly et al. 2012; Milano et al. 2014). However, nothing was known about sinus bradycardia in
KCNQ1 mild mutation carriers, who does not have any
ª 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
599
Autosomal Recessive Long QT Syndrome, Type 1
A. Y. Bdier et al.
clinical phenotype. Bradycardia has been previously
reported in neonates with severe KCNQ1 mutations
(Lupoglazoff et al. 2004). In our study, we did not
observe any cardiac symptoms of LQT1 in the mild
heterozygous KCNQ1 mutation carriers. Such mild mutation carriers may go unnoticed for any possible therapeutic or behavioral intervention as the carriers lack any
cardiac phenotype. Sinus bradycardia in a family member
with sudden cardiac death or unexplained arrhythmia
might lead a physician to consider about the possible carrier status for a KCNQ1 mutation in the family. Another
aspect could also be considered; such mild mutations are
possibly harmless in normal situation, but, such carriers
could have arrhythmia symptoms due to the use of QT
prolonging drugs or under extreme physical or mental
stress, by compromising the repolarization reserve.
In conclusion, we describe a series of patients with AR
LQT1, all originating from consanguineous families in
Saudi Arabia. These mutations could be used for targeted
screening in cardiac arrhythmia patients in Saudi Arabia
and people of Arab ancestry. This study further confirms
that recessive LQT1 patients do not have any deafness but
their QTc are still pronounced and cardiac symptoms are
more severe than the patients with dominant form of
LQT1. Carriers are likely to have bradycardia.
Acknowledgment
This study has been funded by a grant from King Abdulaziz City for Science and Technology (KACST) (10-BIO1075-03).
Conflict of Interest
No conflict of interest declared by any authors of the
manuscript.
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