clinical evaluation and laboratory testing

The Long QT syndrome family of cardiac ion channelopathies:
A HuGE review
(Expanded Web Version)
Stephen M. Modell, MD, MS1, and Michael H. Lehmann, MD2
From the 1Department of Health Management and Policy, University of Michigan School
of Public Health;
Department of Internal Medicine, Division of Cardiovascular Medicine, University of
Michigan Medical System.
Corresponding Author:
Stephen M. Modell, MD, MS
University of Michigan
School of Public Health
109 S. Observatory
Ann Arbor, MI 48109-2029
E-mail: [email protected]
Print version submitted for publication July 27, 2005.
Accepted for publication December 16, 2005.
DOI: 10.1097/01.gim.0000204468.85308.86
Long QT syndrome (LQTS) refers to a group of ”channelopathies” – disorders that affect
cardiac ion channels. The “family” concept of syndromes has been applied to the multiple
LQTS genotypes, LQT1-8, which exhibit converging mechanisms leading to QT
prolongation and slowed ventricular repolarization. The 470+ allelic mutations induce
loss-of-function in the passage of mainly K+ ions, and gain-of-function in the passage of
Na+ ions through their respective ion channels. Resultant early after depolarizations can
lead to a polymorphic form of ventricular tachycardia known as torsade de pointes,
resulting in syncope, sudden cardiac death, or near-death (i.e., cardiac arrest aborted
either spontaneously or with external defibrillation). LQTS may be either congenital or
acquired. The genetic epidemiology of both forms can vary with sub-population
depending on the allele, but as a whole, LQTS appears in every corner of the globe.
Many polymorphisms, such as HERG P448R and A915V in Asians, and SCN5A S1102Y
in African-Americans, show racial-ethnic specificity. At least 9 genetic polymorphisms
may enhance susceptibility to drug-induced arrhythmia (an “acquired” form of LQTS).
Studies have generally demonstrated greater QT prolongation and more severe outcomes
among adult females. Gene-gene interactions, e.g., between SCN5A Q1077del mutations
and the SCN5A H558R polymorphism, have been shown to seriously reduce ion channel
current. While phenotypic ascertainment remains a mainstay in the clinical setting, SSCP
and DHPLC-aided DNA sequencing are a standard part of mutational investigation, and
direct sequencing on a limited basis is now commercially available for patient diagnosis.
Genet Med 2006:8(3):143-155.
Key Words: Long QT syndrome, ion channelopathies, torsade de pointes, epidemiology,
The congenital (also called ”idiopathic”) form of long QT syndrome (LQTS) is
mainly caused by mutations in genes that code for protein subunits of cardiac ion
channels, principally those responsible for the IKs (slow) and IKr (rapid) delayed rectifier
potassium currents. The third most common variant results from a genetic mutation
affecting cardiac sodium channels. The pace of LQTS gene discovery has accelerated
since 1991 when the first genetic locus was identified.1 As of May 2005, 8 major
genotypes, LQT1-8, 471 different mutations, and 124 polymorphisms were described in
the European Society of Cardiology Working Group on Arrhythmias (WGA) LQTS gene
database.2 Among the various LQTS genotypes, the most common feature predisposing
to arrhythmia is prolongation of the ventricular action potential duration during cardiac
repolarization, measured as the QT interval on the electrocardiogram (Fig. 1),3 which can
lead to early after-depolarizations and life-threatening torsade de pointes (TdP)(Fig. 2).4
This converging mechanism has led some to ascribe the “family” concept to the various
LQTS genotypes,5 though considerable heterogeneity exists. Table 1 depicts the range of
genes composing the idiopathic “long QT syndromes” and their corresponding
electrophysiology (Refs. 6-26).
Cellular electrophysiology
The ventricular action potential proceeds through five phases (cardiac action
potential; Fig. 3).5 The initial upstroke (phase 0 - depolarization) occurs through the
opening and closing of Na+ channels. The repolarization process begins with the rapid
transient outflow of K+ ions (phase 1 – Ito current). This is followed by the flow of
outward current through 2 delayed rectifier K+ channels (IKs, IKr) and of inward current
through Ca2+ channels, constituting phase 2 or the plateau phase of repolarization.
Increasing conductance of the rapid delayed rectifier (IKr) and inward rectifier (IK1)
currents completes repolarization (phase 3). Phase 4 represents a return of the action
potential to baseline.27 LQTS mutations act primarily on the IKs, IKr, and INa currents to
prolong the cardiac action potential. The prolongation is registered by an increase in the
heart-rate corrected QT interval, or QTc, on electrocardiographic tracings.3,28 Multiple
studies have shown that prolongation of the action potential can lead to early
afterdepolarizations (EADs) via an increase in L-type calcium current (ICa,L). EADs,
through repetitive triggering and reentry circuits, are considered the most likely
mechanisms for initiation and maintenance of TdP.6
Specific LQTS genotypes
The LQT1 gene (also known as KCNQ1 and KvLQT1) spans 400 kb and encodes
voltage-gated potassium channel alpha subunits. A tetramer of 4 KCNQ1 alpha subunits
co-assembles with the minK gene product (beta regulatory subunit) to form the IKs slowly
deactivating delayed rectifier potassium channel.27 At least 179 KCNQ1, mostly
missense, mutations have been reported.2 KCNQ1 mutations have been identified in the
intracellular (N-terminal and C-terminal), transmembrane, and pore domains of the
encoding gene sequence, with a few in the extracellular domain. For potassium channel
mutations in general, mixed alpha subunit tetramers (wild-type plus mutated units)
exhibit abnormal protein function, producing a dominant-negative effect on ion channel
By itself, the KCNQ1 encoded protein subunit typically induces a rapidly
activating, slowly deactivating K+ outward current (IKs). However in the presence of
minK, KCNQ1 channel activation is slowed down considerably. The net effect of LQT1
mutations is a decreased outward K+ current during the plateau phase of the cardiac
action potential, i.e., a loss-of-function of the ion channel. The channel remains open
longer, ventricular repolarization is delayed, and the QT interval is lengthened.27
The gene for LQT2 (also known as the KCNH2 and human ether-a-go-go--related
or HERG gene) spans 55kb and also encodes potassium channel alpha subunits.
Tetramers of these subunits form the IKr rapidly activating, rapidly deactivating delayed
rectifier potassium channel, which associates with the minK-related peptide 1 (MiRP1)
gene product.27 At least 198 distinct HERG mutations have been identified.2 HERG
mutations are spread in roughly equal proportion throughout the N-terminal, membranespanning, pore region, and C-terminal domains. The majority of HERG pore region
defects are missense mutations, while non-pore defects demonstrate a variety of
missense, nonsense, and frameshift mutations.2,29
The literature on HERG abnormalities describes a variety of structural ion
channel defects, as well as intracellular “trafficking” abnormalities - deficiencies
resulting from subunits that are retained in the endoplasmic reticulum, never reaching the
myocardial cell membrane.30,31 The first type of abnormality, mutant subunits having
dominant-negative effects, can result in a > 50% reduction in channel function.27
Trafficking abnormalities, which also occur in LQT3,32 LQT5,33 and LQT7,34 can result
in a 50% reduction in the number of functional channels (haploinsufficiency) due to
missing protein subunits.29
In terms of electrophysiology, HERG mutations cause potassium ion channels to
deactivate (close) much faster, blunting the normal rise in current (IKr) that results from
rapid recovery from channel inactivation / slow deactivation. The IKr current during the
plateau phase is reduced and ventricular repolarization delayed, leading to QT interval
The LQT3 gene, SCN5A, spans 80kb. At least 56 LQTS SCN5A mutations have
been identified.2 The SCN5A alpha subunit, comprised of 4 sequential domains that fold
end-to-end into a torus-like shape, can form a fully functional channel; beta subunits have
a modifying influence. Normal or wild-type sodium channels open briefly during phase 0
of the cardiac action potential to allow influx of Na+ ions, thus depolarizing the cell, then
inactivate quickly, leaving a small, residual inward current during the plateau phase.
LQT3 mutations lead to the reopening of sodium channels (i.e., gain-of-function) during
this time period, thereby enhancing the inward plateau current and prolonging
The gene responsible for LQT4, 220 kb in length, encodes the ankyrin-B (ANKB
or ANK2) protein.36,37 This “adaptor” protein anchors ion transporters to specialized
domains within the cell membrane, rather than itself transporting ions as happens with the
gene products for the other long QT genotypes. The 5 reported AnkB mutations interfere
with anchoring of Na,K-ATPase and the Na/Ca exchanger, resulting in Na+ build-up and
a compensatory increase in intracellular Ca2+ stores.38 The latter can lead to after-
depolarizations and fatal arrhythmias. A distinguishing feature is that QTc, though
greater than average in groups tested, is inconsistently prolonged.23,38
The relatively small minK gene, mutations in which cause LQT5, is 40 kb in
length. The encoded KCNE1 protein contains a single transmembrane spanning domain
with small intra- and extracellular components. The product of the minK gene forms the
beta subunit of the LQT1 assembly regulating the IKs potassium channel current.
Evidence exists that it may also serve as a modulating factor for IKr channel expression.33
The name “minK” is derived from the now substantiated contention that the gene encodes
the “mimimal” size potassium channel subunit.
The LQT6 gene encoding MiRP1, or minK-related protein 1, is located 70 kb
from minK on the same chromosome.39 The two genes bear many similarities,
suggesting a common evolutionary origin, possibly from a duplication event. Neither
produces a current by itself. The MiRP1 gene product KCNE2 co-assembles as the beta
subunit with HERG alpha subunits to regulate IKr potassium currents. Its structure is
similar to that of minK’s. Mutations in MiRP1 are largely of the missense variety. LQT6
mutations generally lead to only modest QT prolongation.
The LQT7 genotype has been mapped to the inward rectifying potassium channel
gene KCNJ2 on chromosome 17. KCNJ2 encodes the potassium channel protein Kir2.1.
Kir2.1 plays an important role in the generation of inward repolarizing (IK1) currents
during the terminal stages (phase 3) of the cardiac action potential.40 It also anchors the
diastolic resting potential prior to depolarization.41 Kir subunits are believed to form
tetramers in a fashion similar to KCNQ1 and HERG alpha protein subunits. More than 24
mutations affecting Kir2.1 residues have been documented.2,42 Families of mutations
variously affect PIP2 (membrane-associated phospholipid) binding, pore loop function,
and protein trafficking.34,42 Patients generally exhibit relatively modest QTc
prolongation, with case series reporting rare degeneration into TdP and its sequellae.25
Owing to these features plus the characteristic T-U wave pattern, which may lead to
misinterpreted “QT” prolongation, Zhang et al. have questioned the inclusion of KCNJ2
mutations in the LQTS family,24 though the designation is already somewhat established.
More malignant, life-threatening mutations (R67W and C101R) have also been
The most recent addition, LQT8, has been mapped to the voltage-dependent
calcium channel gene CACNA1C on chromosome 12. The expressed exon 8 and 8A
protein product influence voltage-dependent Ca2+ current inactivation. CACNA1C
mutations cause nearly complete loss of L-type Cav1.2 channel inactivation.20,26 The
effect is to prolong the inward (depolarizing) Ca2+ current during the plateau phase
(phase 2), with consequent slowing of repolarization (gain-of-function effect). Marked
QT interval prolongation (as high as 730 ms) and fatal arrhythmias (often in the first 3
years) are characteristic. All individuals tested so far have had de novo mutations.
Multisystemic features of LQT7 and LQT8 will be described in the Disease section.
The literature makes a fundamental distinction between the above LQTS genes
and those factors responsible for QT variation in the general population. Various studies
have postulated major genetic and environmental effects, as well as non-Mendelian
multifactorial effects.44,45 Twin and population-based studies cast a wide net for
heritability estimates of genetic factors explaining QT interval variation in the
freestanding population – between 25 and 60%.44,46-49 A twin and a population-based
study using Framingham Heart Study cohorts have suggested LQT1, 3, and 4 genes as
possible quantitative trait loci in non-LQTS study participants.46,48 While there likely
exists some role for LQT (or other) genes in determining QT variability in the general
population, more work is needed to spell out this relationship.
Patterns in LQTS mutations
We conducted a MedSearch of the LQTS literature from major regions of each
continent for the period 1975-2004 (Tables 2 and 3), and reviewed the mutation and
polymorphism-related citations on the WGA and international Human Genome
Organisation (HUGO) web sites (See Internet sites at end, and Tables 4 and 5). The
mutations Medline search focused on articles including at least one human subject (i.e.,
case studies, case series, or larger); the polymorphisms search contained both human and
nonhuman studies. International LQTS Registry-related (e.g., Italy and the U.S.),
Brugada (see below) and other associated syndrome article searches were conducted
separately. Tables 4 and 5 exclude mutations not referenced in the last 9 years, having
incomplete tabular data, or representing nonfunctional intronic variants. Overall
genotypic data appear separately.
The expanse of human subject-related articles demonstrates the presence of LQTS
in virtually every corner of the globe. Several locales depict unique pockets of activity.
France and Mexico have contributed to the LQT4 and LQT7 literature due to the
presence of large families with rare mutations in each of these countries.36,37,40,52
Mutational site is may affect severity of the LQTS phenotype. In a subset of the
International Long QT Syndrome Registry, patients and kin with LQT2 pore mutations
appeaed to be at a higher risk for cardiac events than individuals with non-pore
mutations.29 On the other hand, certain non-pore HERG mutations can give rise to a
malignant phenotype.53 Though some studies have failed to demonstrate a consistent
difference in phenotypic severity between pore vs. non-pore mutational sites in
LQT1, 54,55 a recent 5-center, 95 patient study in Japan indicated QTc may be prolonged
to a greater extent in pore vs. pre-pore mutations.56 Investigators in the multicenter study
also noted greater risk for patients with transmembrane compared to C-terminal
mutations (55% vs. 21% frequency of cardiac events, p = 0.002). Two studies describing
KCNQ1 mutations in Table 4 tend to support the finding of the multicenter Japanese
study: a study of the mildly presenting C-terminal G589D mutation present in 30% of
Finnish LQTS cases,57 and an investigation of 16 KCNQ1 mutations (15 transmembrane /
1 C-terminal) in 20 families by French investigators.58 However, a mutational screening
survey in the U.S. of 541 unrelated, consecutive LQTS patients performed by Tester et al.
failed to corroborate the above LQT1 and 2 relationships.59 Additional research is
needed to resolve the disparate findings.
Cases and families bearing the same mutation may be separated by considerable
distance, e.g., the HERG A614V missense mutation detected in Japanese families and
multiple unrelated families of European descent,60 and the HERG S818L missense
mutation detected in unrelated families from Belgium and Ireland.61 In many instances
these recurrent genetic events are considered sporadic.62 However, alternative
explanations exist. Tranebjaerg et al., who identified a JLNS R518X mutation on 2
different haplotypes in Norwegian families of Swedish and Scottish ancestry, note the
difficulty of resolving whether the same mutation observed in the different groups is due
to recurrent mutational events or a founder effect.63 Four alleles studied in the Finnish
population – KCNQ1 G589D and IVS7-2A->G (KCNQ1-FinA and B, respectively), and
HERG L552S and R176W (HERG-FinA and B, respectively) – represent founder
mutations enriched by the historic isolation of that country.57,64
In some instances, authors have reported detecting mutational hotspots, coding
regions especially prone to harboring various mutations. The KCNQ1 1022 locus is a
typical example. A C-to-A base pair substitution leads to the A341E missense mutation,
which has been found in at least 4 separate families.2,54 A C-to-T substitution leads to the
A341V mutation, reported in 6 families. Similarly, G->C and G->A base pair
substitutions at the KCNQ1 1032 locus lead to the splicing mutation A344A reported in 8
different families.2,65 Evidence exists that accidental deamination of CpG dinucleotides
at the affected sites may lead to an increased probability of the observed transition and
transversion events.65,66 Individuals bearing these mutations can be either symptomatic
or asymptomatic.65,67
Reported mutational hotspots include KCNQ1 A246V (initially labeled A212V;
reported in USA and South Africa),68-71 A341E and A341V (reported in USA and
France),54,65 A344A (France),65 G589D (Scandinavia);57 HERG A561V (Italy),72,73
SCN5A E1784K (USA),67 1795insD (the Netherlands);51,74,75 and CACNa1C G406R
(USA).20 It is quite possible that some of these “hotspots” depict the movement of
families with common ancestry. For example, the KCNQ1 A246V mutation has been
identified in individuals of European and Japanese ancestry.68 However, de Jager found
that people bearing this mutation in 2 different pedigrees in South Africa shared the same
combination of alleles at 6 linked marker loci, implying that the haplotypes, and the
mutation itself, originated from common Northern European ancestry.69
Whether an alteration achieves a limited or more widespread distribution depends
evolutionarily on the nature of the affected locus. Regions that are conserved throughout
species and that code for an amino acid whose alteration has a severe functional
consequence tend to be less prevalent on a population level.57,76 Conversely, allelic
changes which escape strongly dominant-negative effects to yield partially functional ion
channels, such as the Finnish KCNQ1 G589D mutation,57 the HERG A490T missense
mutation reported in Japan,77 and the KCNE1 V109I mutation described by Schulze-Bahr
in Germany,78 can persist in families and in populations despite being able to trigger
arrhythmias under relatively limited circumstances.
Genotype frequencies
Splawski et al. were the first to calculate relative proportions of the 5 most
prevalent LQTS genotypes (mutations denominator) within the context of a single
clinical study.79 The international listing of allelic mutations in the WGA database can
be used to calculate the most recent figures for all 8 genotypes. The proportion of a
particular genotype within a given set of genotypes is to be contrasted with the frequency
of individuals bearing a particular genotype within the population. Two independent
studies of LQTS patients (total N = 803, patient samples from USA and Europe) allow
calculation of the latter figure, which uses patient population-related denominators.59,79
Table 6 (Refs. 59, 79, 81) includes both sets of figures. Mohler et al. identified 8
individuals harboring ankyrin-B mutations in 664 LQTS probands (7/438 excluding
Brugada syndrome cases), making the LQT4 gene frequency based on a limited case
series low, on the order of 1.6% of LQTS cases.38
In the U.S. study by Tester et al., ethnicity (restrictively defined as the % of white
cases) was 92% for LQT1 positive individuals, 92% for LQT2, 88% for LQT3, and 93%
for the total cohort.59 These figures must be considered a reflection of the patient sample
used, which was accumulated from consecutively seen individuals, rather than a
genotypic or phenotypic feature of LQTS. More refined racial-ethnic profiles of the
various LQTS genotypes (as opposed to allelic variants) are unavailable. Proportions of
patients bearing abnormal alleles, from studies in the U.S. (272 LQTS positive patients)
and the Netherlands plus Belgium (31 LQTS positive), are: 88.2% (95% C.I.: 85.9;
90.4%) heterozygous; 8.6% (4.5; 12.7%) compound heterozygous; and 3.2% (0; 9.6%)
homozygous.59,80 The LQTS literature has only scattered references to homozygosity
rates for specific mutations and polymorphisms, though heterozygous rates for LQTS
polymorphisms are widely reported.
Nearly one third of the individuals in the study by Splawski et al., and 44% of
those in Tester et al., did not test positive for any LQTS mutations, which these and other
authors have ascribed to pretest probability of disease, phenotypic inaccuracy, testing
limitations, and lack of saturation in the range of LQTS genes and mutations yet to be
identified.21,59,79 Calculated frequencies are subject to a variety of potential research
study limitations, including small kindred size (overcome by large patient data sets such
as the International Long QT Syndrome Registry); completeness of genotyping;
differentials in case ascertainment and enrollment (probands alone vs. probands plus
family members, retrospective samples vs. consecutively enrolled patients); and selection
bias (e.g., choice of particular family(ies)).29,81
Patterns in LQTS gene polymorphisms
Table 5 lists population allele (allelic total denominator) or heterozygote
(combinatorial denominator) frequencies for relatively high prevalence LQTS gene
polymorphisms, as well as racial-ethnic breakdowns where they exist. Laitinen reports a
heterozygous frequency of 0.25 and an allele frequency of 0.16 for the HERG K897T
polymorphism in the Finnish population.82 The average allele frequency for the 20
LQT1-3 polymorphisms summarized by Iwasa in Japan was 0.14 (range: .005 to .46).83
Alterations in LQTS protein products associated with genetic polymorphisms
generally exhibit weak suppressive effects in the case of outward potassium currents. For
example, the KCNQ1 G643S amino acid polymorphism found in the Japanese population
leads to a 30% reduction in the slow delayed rectifier current IKs without much alteration
in kinetic properties.84 Reductions in IKr current with the HERG K897T polymorphism
are on the order of 10-30%, leading to only subtle increments in action potential
duration.85 Shifts in the voltage dependence of channel activation in the SCN5A S1102Y
polymorphism identified by Splawski et al. are quite small.86 Oftentimes additional
factors are required for manifestation of symptoms.
Like many LQTS mutations, numerous polymorphisms have been identified in
vastly separate ancestral and geographic populations. Allele frequencies in some
instances may be statistically similar and bear further explanation, as in the SCN5A
D1819D polymorphism shared by the Japanese and Han Chinese (.46 vs. .41,
p > 0.5).83,87 Many of the polymorphisms reiterated throughout studies exist broadly in
their host populations. The HERG K897T and KCNE1 G38S polymorphisms exist in
heterozygous form in more than 7% of each of the four major U.S. racial-ethnic groups
(Caucasian, African-American, Latino, and Asian American), and have been studied
Particular groups may also display higher frequencies of certain allelic variants.
For example, the KCNQ1 variant P448R has been identified in 22 to 28% of subjects in
Japan, but in only 3% of African-American subjects in the U.S., and not in the other 2
racial-ethnic groups.88,90 In the study by Splawski et al., the SCN5A S1102Y
(alternatively known as S1103Y91) polymorphism, which appears to be associated with
drug-related QT prolongation, existed in 13.2% of healthy African-American
cardiovascular study controls. The allele is present in Latino and Caucasian families at
much lower prevalence, and has not been detected in native Chinese.86,87,92 It was also
detected in 19.2% of West African and Caribbean controls, suggesting the route the allele
may have taken on its way to America.86
Systematic racial-ethnic studies have been conducted. Ackerman et al., in looking
at genetic repository samples from 744 healthy individuals representing the 4 major U.S.
racial-ethnic groups, discovered that 86% of the cardiac potassium channel genetic
variants were ethnicity specific. For example, the KCNQ1 G643S polymorphism was
identified at higher rates in African-American and Asian participants (heterozygous
frequencies of 5.9% and 6.0%, respectively) than in Caucasians and Latinos (0% and
1.1%). The heterozygous frequency for HERG P448R was appreciably higher in AsianAmericans (16.4%) than the other groups (next highest: African-Americans – 0.3%).
HERG A915V was identified only in Asian participants (4.5%). Six of the potassium
channel allelic variants that were identified with higher frequency in specific racial-ethnic
categories – KCNE1 V109I and KCNE2 Q9E in African-Americans; HERG N33T,
R176W, P347S, and P917L in Caucasians – have been reported in the literature as
potentially pathogenic.88 In follow-up studies of sodium channel variants in 829 healthy
individuals, 3 of the variants identified that show similar specificities – SCN5A S1102Y
in African-Americans; R1193Q in the Japanese; and V1951L in Latinos – have also been
reported as potentially pathogenic.91 Future areas of investigation involve functional
characterization of variants showing racial-ethnic predilection, and confirmation in
population-based studies.88 Remarkably, a Medline search identified just 5 papers
dealing specifically with cases of LQTS from Africa. Only 1 of them, case 5 in a case
series from Cape Town, mentioned a solitary individual of original African descent.93 In
contrast, a Medline search of cardiovascular and coronary heart disease in Africa
focusing on individuals of African Continental ancestry yielded more than 800 papers.
This gap deserves further attention.
Trends in disease severity
The public health importance of LQTS is highlighted by the fact that it can result
in sudden death, causing as many as 3,000 unexpected deaths in children and young
adults annually in the U.S.6 In the absence of treatment, 6 to 13% of affected individuals
succumb to cardiac arrest or sudden cardiac death (SCD) before the age of 40 years.81,94
Demographic characteristics among patient groups, such as sex, age at first event, and
mean age first seen in clinic for the event, tend to vary by genotype (Table 6).79,81,94,95
The frequency of cardiac events (syncope, aborted cardiac arrest and sudden death) tends
to be higher in individuals with LQT2 mutations than in those with LQT1 or LQT3
mutations. However, a higher percentage of lethal events by age 40 is associated with the
LQT3 genotype.94 Certain families may display a more pronounced phenotype than
others, with a high frequency of syncope and sudden death, especially in the young.96
Detection of probable LQTS in a proband should lead to work-up of other family
members, who are also potentially at risk.97
Inheritance patterns and complexity of disease presentation
Inherited LQTS manifests in 2 different forms. The more common familial form,
referred to as the Romano-Ward syndrome (RWS), displays the cardiac electrophysiologic abnormalities of LQTS and normal hearing. It is inherited in autosomal
dominant fashion. The exact prevalence is unknown, but is frequently approximated at 1
gene carrier in 7,000 persons in the general U.S. population.6 A critical single gene
mutation in any one of the various LQTS genotypes (particularly LQT1-3) can lead to
RWS. Mutations characteristic of RWS tend to act in a dominant-negative manner (K+
channel mutations) or cause haploinsufficiency (no functional interaction between wildtype and mutant proteins), resulting in half the expected current (SCN5A mutations).
The second familial form, Jervell and Lange-Nielsen syndrome (JLNS), is
associated with homozygous KCNQ1 and KCNE1 mutations. JLNS is characterized by
marked QT prolongation with a high incidence of sudden death and bilateral sensorineural deafness. The latter is a consequence of developmental abnormalities in the
endolymph-producing stria vascularis of the cochlea, resulting in potassium level
disturbances in the inner ear fluid.98 Prognosis is generally worse than with RWS due to
the presence of 2 copies of the same allele.6 (Rare JLNS cases with 2 different KCNQ1
alleles have also been reported.9,99) The cardiac component is inherited in autosomal
dominant fashion, but low penetrance (25% in one 3-generation study) in parents of
probands may mimic autosomal recessive transmission.72,99-101 The characteristic of
deafness is inherited as an autosomal recessive trait. JLNS is fairly rare in the general
population; 1 study estimated the prevalence in children aged 4 to 19 years in England,
Wales and Ireland to be 1.6 to 6 per million.63 Prevalance of JLNS in the congenitally
deaf ranges from 0.57%102 to 6.5%103.
As indicated in Table 4, a number of mutations leading to JLNS – 572-576del and
R518X in KCNQ1, and D76N in KCNE1 – have received widespread attention. Tyson et
al. note that frameshift / truncating mutations affecting the C-terminal domain of KCNQ1
represent a large number of JLNS mutations, in contrast to the more prevalent missense
mutations of RWS, spread throughout a variety of domains.104
Double mutants (homozygotes) of LQT2 and 3, yielding ion channel knock-outs,
exhibit a more severe phenotype than their single gene counterparts, and can result in
intrauterine and neonatal complications.10-14 The effect of a given mutation can be
potentiated when existing in combination with a second mutation in a separate LQTS
locus (e.g., the mild SCN5A A572D mutation co-existing with a more serious KCNQ1
V254M mutation).61,105 Compound heterozygous states represent variations on the
cardiac cell’s ability to form functional protein subunits in individuals carrying two
different alleles. The associated phenotypes lie midway, in terms of degree of QT
prolongation, frequency and severity of cardiac events, between those of RWS
(1 functional mutation), and the haploinsufficiency connected with homozygous
Relatives of individuals with 2 variant gene copies display variable phenotype.
They may have normal to prolonged QT intervals (generally less prolonged than the
homozygous or compound heterozygous proband), and may or may not experience
syncopal episodes and arrhythmias.7-9 The frequency of fatal cardiac arrest in relatives is
less than that of probands, but greater than zero. The variability in presentation of
mutation-carrying family members of compound heterozygous probands, and the
existence of subtle electrophysiologic effects in individuals lacking overt
symptomatology, present a challenge when trying to apply the classical distinction
between dominant and recessive mutations to ion channelopathies.106 The higher-thanexpected proportion of compound heterozygotes in some recent studies is an additional
piece of evidence suggesting the prevalence of LQTS gene carriers in the general
population may be much higher than generally accepted.8 Testing that stops at the first
mutation in a detected proband can fail to identify compound heterozygotes and could
leave carrier relatives undiagnosed.8,61,105
As with JLNS patients, LQT 7 and 8 patients exhibit extra-cardiac abnormalities.
The triad of manifestations stemming from KCNJ2 mutations (LQT7) includes
ventricular arrhythmias, periodic paralysis, and skeletal developmental abnormalities
(Andersen syndrome; AS). The latter include short stature, scoliosis, facial abnormalities,
and syndactyly (webbing of the hands and feet).40 Though dysmorphic features occur in
more than ¾ of cases,25 penetrance is variable, and several reports exist of families with
periodic paralysis and arrhythmias but lacking the gross physical characteristics of
AS.107,108 LQT8 is more strikingly multi-systemic, leading to congenital heart disease,
syndactyly (depending on the mutation), immune deficiency, intermittent hypoglycemia,
developmental delay, and autism (Timothy syndrome; TS).20,26
Brugada syndrome, progressive cardiac conduction defect disease (PCCD), and
sudden infant death syndrome (SIDS): Other SCN5A-related disorders
For the disease associations search, we used the results of the gene database
searches together with more focused searches employing the subject headings below.
Several SCN5A review articles were also quite useful.59,109,110 SCN5A mutations display
the most striking phenotypic pleiomorphism of all the genotypes. The complexity of the
cardiac ion channelopathies in general, demonstrated in the relationships below, is
increasingly appreciated.111
Brugada syndrome is characterized by ST-segment elevation in the right
precordial leads (V1 to V3) and, in some patients, right bundle-branch block, with
propensity for ventricular fibrillation and sudden death, often nocturnally.112 The
incidence varies between 5 and 66 persons per 10,000 in well-studied Asian areas, but is
thought to be much less in the United States and Europe.113 In Southeast Asia, where it is
endemic (and believed to be a cause of “sudden unexplained nocturnal death syndrome”
(SUNDS)), the disorder shows a male predominance (8:1 male:female ratio) and an
average onset of 40 years (range 2 days to 84 years globally).112,114
Like LQTS, Brugada syndrome is transmitted in autosomal dominant fashion with
incomplete penetrance. Sporadic cases have also been reported. The two syndromes are
distinguished by their electrocardiographic (ECG) profiles and for identified mutations,
the quickly inactivating sodium channel currents of Brugada, contrasting with the
persistent noninactivating currents of LQT3. In 1998 Chen et al. identified 2 different
C-to-T base substitutions, leading to SCN5A R1232W and T1620M mutations, in all 6
affected members (lacking in 150 nonspecified controls) of a family having cases of
idiopathic ventricular fibrillation.115 Large, 3- to 8-generation kindreds have also been
examined for SCN5A mutations.75 SCN5A article reviews list 67 Brugada syndrome
mutations overall, of which 49 are distinct to Brugada syndrome alone, the remaining
being shared with other SCN5A syndromes.51,109 Four SCN5A mutations –
D1114N,79,116 delK1500,110,117 E1784K, 67,79,110 and 1795insD75,79 – exhibit
electrophysiologic profiles of both Brugada syndrome and LQTS. A 2002 series by Priori
et al. detected SCN5A mutations in only 28/130 (22%) of Brugada syndrome probands,
however, suggesting further genetic heterogeneity.110
PCCD, also called Lenegre-Lev’s disease, is one of the most common cardiac
conduction disturbances, which cause disability in millions of people worldwide and
often lead to pacemaker implants.118 PCCD is characterized by progressive, age-related
slowing of cardiac conduction through the His-Purkinje system, right or left bundle
branch block, and prolongation of the PR rather than the QT interval. Patients are at risk
for development of high-grade atrioventricular block, syncope, and potentially, sudden
death. Linkage analyses in a Dutch and large French family by Schott et al. led to the
identification of an SCN5A T-to-C substitution in the highly conserved +2 donor splicing
site of intron 22 (IVS22+2 T->C).119 Tan et al. followed with the identification and
functional characterization of a second responsible SCN5A mutation, G514C, in a family
with 5 affected members.118
Investigators have sequenced additional SCN5A mutations displaying PCCD in
combination with LQT3 (delK1500),117 Brugada syndrome (S1710L, G1406R),120,121
atrioventricular block (G298S and D1595N),122 sick sinus syndrome (G1408R),123 and
even dilated cardiomyopathy (D1275N).124 The association with LQT3 is evidenced by
17 gene carriers in a 4-generation kindred with the delK1500 mutation having an
electrocardiographic presentation overlapping PCCD and LQTS, as well as Brugada
syndrome.117 The appearance of isolated cardiac conduction defects and Brugada
syndrome in different collateral branches of a large French family led Kyndt et al. to
suggest the influence of modifier genes in governing SCN5A phenotype.121 Proximal
changes in base character or position can also be critical, as a change in one base pair can
result either in LQT3 (Y1795C mutation)125 or Brugada syndrome (Y1795H),110,116,125
and a minute positional difference in the same base substitution can lead to either PCCD
and Brugada syndrome (G1406R)120,121 or PCCD and sick sinus syndrome (G1408R).123
Other SCN5A sites reveal a similar protean character.62 This subtle mutability illustrates
the relatedness of the various SCN5A-related syndromes.
SIDS, sudden unexpected infant death below 1 year of age, is a multifactorial
phenomenon with numerous putative causes, including LQTS. The incidence of SIDS is
1.6 per 1,000 live births in the United States, and 0.7 per 1,000 in Italy.126 Two Italian
studies – a single center prospective ECG study of 1,830 newborns completed in 1991,127
and a national multicenter study of 33,034 newborns completed in 1998128 – have
demonstrated significant differences in mortality rate between newborns with and without
a relatively prolonged QT interval. In the second, larger study, 50% of the infants who
died of SIDS had a QTc interval > 440 ms, which increased the risk of SIDS by a factor
of 41.3 (95% C.I.: 17.3 – 98.4). Wren, however, argues that not all international studies
have demonstrated an excess of sudden infant deaths in long QT families.129 Further
complicating the picture, the studies drawing cases from the International LQTS
Registry, to which Wren refers, may encompass patients older than 1 year of age and
with a wide variety of mutations.95,130
LQTS-specific mutations in the SCN5A gene have been detected in aborted neardeath and postmortem SIDS cases by 4 investigative teams.131-134 S941N, A1330P, and
M1766L mutations have been identified in single cases, providing suggestive evidence of
a SIDS-LQTS link.131,133,134 A prospective study by Ackerman et al. in the U.S. of
medical examiner’s office SIDS cases found A997S and R1826H mutations in 2 of 93
medical examiner frozen tissue samples, suggesting a possible association of LQTS with
2% of SIDS cases.132 Evidence also exists that phenotypically severe Brugada syndrome
mutations such as L567Q may be involved in SIDS.116,135 However, the LQTS
association is further strengthened by the observation of SIDS cases in 2 Italian families
with the KCNQ1 mutation P117L,136 and of a 7-week-old SIDS victim with the novel
HERG mutation K101E.137 These investigations suggest LQTS mutations play a role in
the etiology of SIDS, though not as a singular cause. For example, ECG assessment of
sleeping infants has not demonstrated any relation between body position (strongly
related to SIDS risk) and QTc interval that might correlate the 2 factors.138
2:1 Atrioventricular (AV) block: Association with SCN5A and HERG
Instances of second-degree AV block in infants came to light early on in case
studies of LQTS.139 The 2:1 AV block that can accompany LQTS results from a
prolonged electrical recovery time in His-Purkinje and/or ventricular tissues exceeding
the sinus cycle length, rather than innately impaired conduction as seen in PCCD. AV
blocks in LQTS patients are of great concern because of bradycardia-induced further
lengthening of the QT interval to values often in excess of 600 ms, with increased risk of
TdP and sudden death. In a 26-center, 287 LQTS patient international collaborative
study, mean age 6.8+-5.6 yrs., 5% of patients were found to have significant AV block;
13 of these 15 individuals displaying 2:1 AV block, and 2 complete heart block. Fiveyear mortality rates were estimated at 27 to 44% for treatment compliant individuals.140
Two cases have been reported of SCN5A mutations (G298S, D1595N) possessing
inactivation dynamics distinct from both LQTS and Brugada syndrome.122 However,
SCN5A mutations – P1332L,142 M1677L,131 V1763M,142 V1777M (homozygous),14 and
homozygous HERG mutations – L552S,11 exon 4 bp558-600 duplication,12 have also
been documented in instances of 2:1 AV block in families with LQTS. Significant AV
block and/or bradycardia detected in the fetus may warrant further diagnostic workup and
Familial atrial fibrillation and short QT syndrome: Associations with KCNQ1,
Atrial fibrillation has a mean prevalence of 0.89% in the U.S., increasing to 5.9%
over age 65. It accounts for one third of strokes in patients over age 65. An initial study
by Brugada et al. of a family in Spain and 2 other smaller families suggested possible
linkage to chromosome 10q22-q24.144 A 2003 study of a 4-generation family with
familial atrial fibrillation in Shandong Province, China implicated the KCNQ1 S140G
missense mutation, with QTc ranging from 450 to 530 ms.22 However, atrial fibrillation
as well as inducible ventricular fibrillation have been observed in 3 European families
with QTc <= 260 ms, characteristics of the short QT syndrome.145,146 Reports are
emerging of associations with the LQT1, 2, and 7 genotypes.15-17 Electrophysiologic
studies of the HERG N588K mutation have shown failure of IKr-related channels to
inactive (i.e., to rectify). Consequently, repolarizing currents increase during the early
phases of the action potential (AP)(gain-of-function), leading to AP abbreviation and
shortening of the QT interval.16 While families bearing this mutation have demonstrated
atrial fibrillation, not all of the mutations detected so far have done so, indicating the
need for further characterization of the syndrome.
Asthma: A pulmonary association
A retrospective analysis of 713 LQTS families enrolled in the International LQTS
Registry has also disclosed an association between LQTS in general and asthma.147
Asthma was identified in 220 (5.2%) of 4,310 family members. The study uncovered an
almost twofold higher prevalence of asthma among LQTS-affected patients than their
borderline QT interval or unaffected family members (7% vs. 4%; p < 0.001). The
investigators controlled for the effects of beta-blocker medications.
Clinical disorders with secondary (acquired) LQTS
QT prolongation associated with heart failure is a common, acquired form of the
syndrome.41 Experimental studies have shown the electrophysiologic remodeling
accompanying ventricular hypertrophy and cardiomyopathy can lead to increased action
potential duration, early afterdepolarizations, and fatal polymorphic ventricular
tachycardias.41,148,149 Large-scale epidemiologic studies have demonstrated an
association between QTc prolongation and cardiac prognosis in patients with heart
disease, though many studies are methodologically incomplete, lacking appropriate
adjustment for prior conditions.150 QT interval prolongation has also been described in
cirrhosis (with and without alcohol), related to the degree of liver dysfunction and
resolving upon liver transplantation.151,152 It may also occur on an acute basis with other
medical conditions, such as myocardial ischemia, hypothermia, hypothyroidism,153
pheochromocytoma,154,155 and subarachnoid hemorrhage,155,156 subject to various
modifying factors.
Gene-gene interactions
Two major studies, N >= 250 each, have noted variable QTc and ST-T-wave
patterns in individuals having the same LQT1-3 genotype and among family members
with the same mutation.21,157 The complexity of clinical and ECG presentation in LQTS
has prompted authors to impute the involvement of one or more modifier genes.21,157,158
Interaction between LQTS loci is another plausible explanation.
Empirical evidence for gene-gene interactions comes from observations of
different protein complex subunits and of multiple allelic variants operating together.
Chouabe et al. noted a range of reductions – from 28-97% – in the steady state current
when KCNQ1 mutations were co-expressed with wild-type minK regulatory subunits,
compared to minor changes when expressed alone.99 Analogous observations have been
made for the SCN5A D1790G mutation and its beta regulatory subunit.159 Tinel et al.
found that the current generated by wild-type KCNQ1, when co-expressed with a
KCNE2 Q9E mutation in a patient with drug-induced arrhythmia, was decreased by 85%
compared to KCNQ1 alone.160 Heterozygous KCNQ1 V310I and R594Q mutations
reduce ion channel current by about 30%. However, when either KCNQ1 mutation is
present together with the KCNE1 D85N polymorphism in the same individual, current
can be reduced 60-75%.7
Some interactions may be relatively common. For example, the SCN5A Q1077del
ubiquitous splice variant (estimated population frequency: 65%) may coexist with the
SCN5A H558R polymorphism present in heterozygous form in approximately 30% of
individuals in the general population, and in homozygous form in approximately 5% of
individuals. Patch clamp measurements of transfected cells suggest INa current densities,
together with a more positive voltage dependence of inactivation, may be reduced 17.5%
in H558R heterozygotes and 35% in homozygotes also possessing the splice variant.161
Several other variants also display either an alteration in current density or shifts in
channel activation, inactivation, or recovery in the presence of Q1077del. The changes
are not predictable or uniform, thus warrant further investigation.162 In contrast, when
H558R coexists in an individual bearing an SCN5A M1766L mutation, the
polymorphism rescues the latter mutation from causing a trafficking defect.163
Investigators have proposed a “double hit” hypothesis for the compound effect of
different genetic alterations in the manifestation of LQTS, an idea traditionally used by
cancer researchers.7,8,163 Impaired interaction with facilitating proteins has also been
invoked as an explanation for the 40% of AS cases lacking identifiable KCNJ2
Triggers for Torsade de Pointes in congenital LQTS
Three types of external stimuli – physical exercise, loud noise, and psychological
stress – are widely recognized triggers of LQTS symptomatology. A survey by Schwartz
et al. of 670 patients in the International LQTS Registry revealed genotype-specific
patterns in the type of trigger responsible for LQTS cardiac events.18 Sixty-two percent
of events in LQT1 patients occurred during exercise, especially swimming, and 43% of
events in LQT2 patients were connected with episodes of emotional stress (fear, anger).
In addition, sudden intense auditory stimuli, e.g., elicited by alarm clocks or phones,
often accompanied LQT2 cardiac events.18,164 LQT3-associated arrhythmic attacks
occurred predominantly during rest or sleep (39%). Series from the Mayo Clinic in the
U.S.A. and clinical centers in the Netherlands provide supportive data for these
observations.165,166 The differential effect on ventricular repolarization of genotypespecific ion currents and of sympathetic activity have been proposed as the source of this
Caution must be used in the interpretation of triggers to deduce LQT genotype, as
the various triggers are not necessarily unique to any one genotype. It is also important to
note that catecholaminergic polymorphic ventricular tachycardia (CPVT) associated with
cardiac ryanodine receptor mutations should be considered whenever LQT1 is excluded
in cases of exercise (especially swimming)-induced arrhythmia. CPVT behaves like an
LQT1 phenocopy, but without the QT prolongation.167,168
Sex and age-sex modulation of phenotype
Sex is an important intrinsic factor in disease etiology and cardiac risk
stratification for LQTS patients and their families. Pathbreaking work by Hashiba in
Japan revealed a preponderance of females among RWS patients; greater QT
prolongation and more severe outcomes in females; and earlier onset of syncope in
males.169 Family studies have shown that QTc tends to shorten in males during
adolescence, with no corresponding changes in female QTc intervals during this
period.170,171 A study by Zareba et al. of 533 cases selected from the International LQTS
Registry further demonstrated that the risk of cardiac events is significantly higher during
childhood (age <= 15 yrs) for LQT1 males compared to LQT2 females. However, during
adulthood, LQT1 and LQT2 females have a significantly higher risk of cardiac
complications than males of the same genotype (hazard ratios = 3.35 (95% C.I.: 1.40;
8.02) and 3.71 (1.37; 10.07), respectively).95 A contemporaneous study by Priori et al.
showed a more severe prognosis for female LQT2 patients and for male LQT3 patients
before the age of 40 years.81 The repeated observation by investigators of age-sex
modulation of the QT interval (both in normals and LQTS patients) and of LQTS-related
symptomatology points to a hormonal influence.170-173 Androgenic protective
effects,171,174,175 as well as relative progesterone and estrogen levels in females176 may be
Sex has also been postulated as a modifier of gene expression and drug-gene
interaction. In a Finnish population-based study, the QTc interval was shorter in females
with the HERG K897T polymorphism AA genotype (441+-69 ms) than in females with
the AC or CC genotypes (477+-99 ms, p = 0.005), whereas no analogous significant
differences appeared in males.89 A comparable gender difference was found in a second,
Dutch study which disaggregated QTc means for the 3 genotypes.177 Studies looking at
patients on QT-prolonging cardiovascular medications (e.g., quinidine, amiodarone,
sotalol)178-180 as well as certain noncardiovascular drugs (e.g., erythromycin, cisapride,
probucol)181,182 have noted an increased risk faced by women for TdP beyond expected
prevalences. QT prolongation resulting from intake of antiarrhythmic agents such as
ibutilide can also be enhanced during menses and ovulation.176
Drug-induced LQTS
A variety of observations, such as susceptibility of patients’ first-degree relatives
to drug-induced QT interval prolongation, point to a close mechanistic connection
between the inherited and acquired forms of LQTS.183-185 Practitioners actually
encounter acquired forms of LQTS, brought on by medications and electrolyte
abnormalities, more often than the inherited form. Acquired LQTS is a potentially lifethreatening problem that is international in scope.186 The incidence of TdP with
antiarrhythmic use varies from 0% to ~8% depending on the particular drug and, in some
cases, dose.155 Much less commonly, certain types of noncardiac medications –
antipsychotics (e.g., thioridazine), methadone, antimicrobials (e.g., erythromycin), the
gastrointestinal stimulant cisapride, and antihistamines (e.g., terfenadine) – may induce
QT-prolonging drugs characteristically directly block IKr potassium channels,
creating an “LQT2” phenotypic equivalent.190 In exceptional instances, the drugs may
interfere with HERG protein trafficking.191,192 One study estimated the odds ratio for
cardiac events at 1.93 (95% C.I.: 1.89-1.98) for each unit increase in HERG blocking
activity.193 Ancillary drugs may inhibit liver or intestinal cytochrome function (CYP3A4
in the case of erythromycin and cisapride; CYP2D6 for thioridizine), reducing clearance
and critically increasing parent drug concentrations that could block potassium
channels.3,187 Drug effect on potassium channels may also be potentiated by a variety of
milieu-related factors, such as hypocalcemia, hypokalemia and hypomagnesemia related
to diet,61 medical conditions,84 diuretic use, and recent cardioversion of atrial fibrillation
causing sudden heart rate slowing.155
A concern is that phenotypically normal individuals harboring “forme fruste”
(clinically inapparent, low penetrance) mutations may escape detection and be exposed to
potassium channel blocking drugs at some point, placing them at risk for TdP.58,72
Research teams have uncovered mutations in several LQTS genes that could predispose
individuals to drug-induced TdP: KCNQ1 – Y315C,194 R555C,58 R583C;90 HERG –
P347S,184 R784W;90 SCN5A – L1825P,195 S1102Y;86 KCNE1 – V109I;78 and KCNE2 –
A116V,184,196 M54T, I57T.197 In a study of 92 patients exhibiting marked drug-induced
QT prolongation, Yang et al. were able to identify allelic variants in 10-15% of affected
individuals.90 Combinations of risk factors may act in concert to compromise the heart’s
repolarization reserve, i.e., its capacity to recover from cellular depolarization.198
Administration of QT prolonging anti-arrhythmic drugs should be considered hand-inhand with the patient’s sex, presenting arrhythmia, and type and extent of compromised
cardiac function.179 Detection of drug-related polymorphisms in individual patients
might eventually be useful in the assignment of risk and implementation of preventive
measures. The known ability of HERG to bind with such a broad array of drug moieties,
with attendant risk of QT prolongation and TdP, has great importance for drug
development and its regulation by government agencies and the pharmaceutical
Phenotypic ascertainment: Clinical and baseline ECG diagnosis
Patients are ascertained for the presence of congenital LQTS for a variety of
reasons. About 30% of patients are initially identified during more conventional clinical
evaluation of unexplained syncope or aborted sudden death, 60% when affected family
members undergo a screening ECG, and 10% under varied clinical circumstances.200
Seizures from transient arrhythmia-associated cerebral anoxia may prompt a
misdiagnosis of “epilepsy.” The residuum of patients in whom the diagnosis of LQTS is
missed remains at increased risk, with a recurrence rate for cardiac events, mainly
syncope, in the range of 4-6% per year.200 Follow-up diagnostic procedures include 24-
hour ambulatory (Holter) ECG monitoring, exercise testing, and confirmatory genetic
testing (typically when family mutations are already known).97
A scoring system for separate diagnostic items (where 3 points = an item
indicating greatest likelihood of LQTS, such as QTc >= 480 ms; and 0.5 points = an item
indicating least likelihood, such as congenital deafness), based on case and family
history, symptomatology, and ECG has been developed. The summed clinical point score
(or “Schwartz score”) allows patient classification into low (<= 1 point), intermediate,
and high (>= 4 points) risk groups.201 Several studies have suggested that syncope might
be a weaker indicator than previously thought, as it does not automatically point to the
occurrence of TdP in persons under consideration of being at risk for LQTS.157,158,202-2064
Nonetheless, the discovery of a prolonged QT interval following a syncopal event in the
absence of structural heart disease or exogenous causes suggests the diagnosis of
A QTc exceeding 450 ms in men, or 460 ms in women and children (top 5% of
the normal QTc distribution curve), is considered prolonged.97 This contemporary
definition is more clinically practical than the traditional 440 ms cutoff value,200 which is
less specific. Table 7 (Refs. 204-217) provides averaged figures on the statistical
accuracy of using the QTc interval alone to assess carrier status versus adaptations of the
clinical scoring system combining ECG with clinical history. The sensitivity of both
approaches is around 70%. The greatest specificity appears to derive from clinical
judgment incorporating ECG findings. Careful consideration of history, presentation, Twave morphology, and the use of QT intervals provide complementary information.
Computer-generated ECG measurements and interpretation can seriously
misclassify at-risk family members, especially with regard to LQT1 variants, which can
be challenging to diagnose because of the often normal appearing T-wave morphology.21
The Task Force of the International Society for Holter and Noninvasive
Electrocardiology recommends that all automated computer interpretation of data should
have operator review, while others urge independent calculation of QTc by the operator
when computers are used.28
Notched or bifid T-waves, and overt T-wave alternans are both cited in
Schwartz’s diagnostic criteria for LQTS.201 Lehmann et al. found T-wave humps in 12 of
13 LQTS families. Statistically significant differences were detected in the frequency of
T-wave humps by QTc category, though they were also present with borderline (420-460
ms) QTc, making them a useful phenotypic marker.218 We now appreciate this feature to
be much more frequent in LQT2 than LQT1 and LQT3 patients.21,219,220 Other ST-Twaveform patterns, as described in Table 1, may point to LQT1 or LQT3 variants.21,221
Investigators have expressed mixed opinion on the diagnostic and prognostic
value of T-wave alternans, variation in morphology of ECG complexes on an everyother-beat basis.222 Overt T-wave alternans – grossly visible beat-to-beat variation in Twave amplitude and/or polarity – is viewed as an important prognostic indicator for TdP
and sudden cardiac death in LQTS patients.223 However, it is only reported in 2.5%
(LQTS general)224 to 7% (LQT2)29 of LQTS study participant samples. In contrast,
microvoltage T-wave alternans (identifiable only by special signal processing during
heart rate acceleration) has been observed in 18-45% of LQTS patient groups undergoing
exercise stress testing or 24-hour Holter monitoring.204,225
Another repolarization parameter, QT dispersion - the difference between the
maximum and minimum QT values across the 12 standard ECG leads - has led to
inconsistent results in distinguishing symptomatic from asymptomatic patient groups,
shows poor intra- and interobserver reproducibility, and fails to take into account T-wave
morphology.207,226,227 The physiologic significance of QT dispersion has also been
seriously questioned.228 In contrast, investigational measures which reflect the full
character of the T-wave, such as principal component analysis, have achieved gains in
sensitivity and specificity in the diagnosis of LQTS.211,230
Phenotypic ascertainment: Other diagnostic tests
Clinicians and investigators use ambulatory 24-hour Holter ECG monitoring to
increase the ability to identify actual LQTS cases among individuals with QTc
prolongation.97 Overt T-wave alternans, bradycardia due to intermittent sinoatrial block,
and transient episodes of ventricular tachycardia and TdP may occasionally be picked up
in patients with suspected LQTS.230 Derived QT:RR (cycle length) relationships can
also be dynamically examined.28,231 Exercise ECG stress testing is used to supplement
the evaluation of suspected cases as well as assess the effectiveness of beta-blocker
therapy. The QT interval may become unequivocally prolonged during the exercise
recovery phase, particularly in LQT1 mutation carriers.213 Absence or blunted
development of QT interval shortening during exercise tends to be less specific for
LQTS.97 Both of these techniques can aid clinicians in distinguishing LQT1 from LQT2
Epinephrine infusion has been investigated as another provocative test in known
or suspected LQTS. Studies have shown differential response of LQT1, 2, and 3 patients
to epinephrine infusion.219,233,234 Epinephrine challenge is considered a powerful test to
unmask low-penetrance KCNQ1 mutation carriers.214 A number of nonpharmacologic
positional and other maneuvers affecting autonomic tone have also been studied, to a less
rigorous degree, as possible inducers of the LQTS phenotype.235-237
Genetic testing
Genetic testing has so far largely been relegated to research studies, making the
phenotypic and non-molecular genotypic tests cited above the mainstay of clinical risk
assessment.97 The recent commercial marketing of short turn-around time (~ 6 weeks)
long QT syndrome genetic diagnostic testing, for example, Genaissance Pharmaceutical’s
FAMILION Test,238 and increasing availability of testing through university-affiliated
laboratories in several countries, could establish genetic testing as a clinical tool.
However, before widespread use, the clinical (as opposed to analytic) validity of LQTS
genetic testing needs to be more widely established. About 60-75% of LQTS patients
have an identifiable LQTS-causing mutation present in one of the 5 most prevalent
cardiac channel genes (KCNQ1, HERG, SCN5A, KCNE1, KCNE2), the latter percentage
deriving from screened patient groups with a predetermined high probability of being at
Genomic DNA in LQTS mutational analyses is typically derived from peripheral
blood lymphocytes, more rarely buccal swabs. LQTS studies generally make DNA-based
diagnosis more cost-efficient by employing single-strand conformational polymorphism
(SSCP) analysis and denaturing high performance liquid chromatography (DHPLC) as
initial screens. These methods limit the need for direct sequencing to a few abnormal
polymerase chain reaction (PCR) products.215 SSCP is often the method of choice due to
simplicity. In the general genetics literature, SSCP sensitivity for detecting true
mutations ranges from 75-98%,240 though articles concentrating on SSCP for familial
hypertrophic cardiomyopathy cite sensitivity values of 95-98%, with 97-100%
specificity.214,215 The sensitivity of DHPLC for LQTS mutations has also been estimated
at 95%.217 One article testing SSCP on short KCNQ1 “core proteins” from 15 in vitro
constructed mutants reported achieving a sensitivity of 100%.241 DNA fragment size,
assay temperature, and experience of the performing laboratory are major factors cited, in
addition to technical and biochemical considerations.215,240 Many research studies
follow-up with functional investigation comparing wild-type and mutant cDNA
constructs using voltage patch-clamp techniques in various expression systems, e.g.,
human embryonic kidney cells, heterologous mammalian cell lines or Xenopus oocytes.
A trial involving DNA sequencing (1500 reference alleles) of samples from a
DHPLC-negative subset of LQTS referrals to the Mayo clinic was able to find mutations
in an additional 7/46 (15%) of cases.217 Commercial LQTS testing employing direct
sequencing would, therefore, be limited by non-inclusion of LQT4, 7, and 8, and by the
existence of private mutations in samples that do not appear in the LQTS reference
databanks used by the commercial laboratory.59 The issue of how mainstream LQTS
genetic tests will be provided and interpreted – via physician, genetic counselor, or direct
consumer marketing – needs to be addressed.242
Genetic screening of specific populations
LQTS population screening programs are shaped by existent facilities and
whether particular highly prevalent mutations have been identified within a given
country. The presence of the Statens Serum Institute in Denmark has facilitated inclusion
of LQTS patients into a mutations-based national long QT registry.243 In a country where
several major LQTS mutations are due to founder effects, facilities at the University of
Helsinki have been able to identify the KCNQ1-FinA and HERG-FinA mutations in
~35% of LQTS cases. A battery of the 4 founder mutations mentioned earlier could
potentially identify 69-73% of Finnish cases.64 In China, ECG screening using ST-Twave patterns to determine genotype is regularly performed on new entries into the
national LQTS registry.244
Investigators in Japan,76,83 Belgium,184 and Germany245 have conducted
systematic screening of clinical and population-based groups for acquired LQTS-related
polymorphisms in their respective countries. Genetic screening of particular subgroups
showing susceptibility to LQTS could also be a part of future clinical programs. In their
study of the SCN5A S1102Y polymorphism, Splawski et al. concluded that the greatest
risk lies in the effect of concomitant factors – medications, hypokalemia, and structural
heart disease – on the cardiac action potential.86 The authors note the increased
prevalence of the variant in African-Americans and suggest testing as part of future
preventive strategies in those at risk. Longitudinal studies would be required to confirm
the predictive utility of such testing, however.
The drive to move testing for LQTS to the population level should also be
accompanied by appropriate analysis of the social and ethical issues involved. The
suitability of using racial-ethnic background as a proxy for drug responsiveness and
toxicity is already a subject of debate in the area of pharmacogenomics.246 Now that
articles have appeared looking at LQTS genetic variants in multiple racial-ethnic
groups,86,88,91,92,247 the same sorts of controversies are bound to emerge.
Newborn screening
Prenatal genetic testing for congenital LQTS has so far occurred only in the
investigational setting with limited numbers of cases.143 Testing for LQTS in newborns
typically takes place with referral for ECG abnormalities, such as 2:1 AV block and sinus
bradycardia.143,248 Workup can involve either ECG alone,139 or in combination with
mutation testing.10,12,248 Preliminary data from a prospective study assessing QTc in
50,000 consecutive neonates has shown that newborn population screening for LQTS is
possible, though overall feasibility is uncharted.249
While bodies such as the European Society of Cardiology have advocated
neonatal ECG inspection as a step towards SIDS prevention,250 consensus in this area is
not yet established. In the study by Schwartz et al. showing a high proportion of infants
with QTc > 440 ms among SIDS fatalities,251 2.5% of the newborns with QTc > 440 ms
did not suffer from SIDS, and would be considered false-positives using this criterion.252
Positive predictive value was low – 1.4%. One hundred infants would need to be placed
on beta-blockers to save 2 lives, with compliance being less than guaranteed.253
Strategies such as repeat screening for particular QTc thresholds have been advised to
reduce the number of false-positives inappropriately treated,126,253 but the cost of
purchasing monitoring devices for vast numbers of infants must also be born in mind.254
Family screening
Family history can serve as a useful initial screening device to identify potentially
at-risk individuals on a population basis. In a study of 37 patients being treated for
congenital LQTS, 14 individuals (38%) had a positive family history; the remaining cases
being considered sporadic.255 Asymptomatic children and adults with a family history of
LQTS, family members who have experienced the unexplained sudden death of a young
person, and relatives of patients with known LQTS should be considered at-risk. Further
work-up of at-risk family members may be performed either through mutation testing or
ECG. In the search for meaningful predictor variables for family members, neither the
QTc nor the severity profile of LQTS in probands (history of aborted cardiac arrest or
sudden death) have turned out to be predictive of parents or siblings undergoing a “first
cardiac event”.256 Several studies have singled out the QTc of the family member
him/her-self as a significant predictor variable of personal risk.204,256 Priori et al. have
successfully used a scheme based on QTc, sex, and genotype to divide patients into high,
intermediate, and low risk levels.81
A perennial obstacle is that gene carriers and noncarriers share a significant
region of QTc overlap, particularly in the broad QTc “borderline” band of 420–450/460
ms. Seventy-eight percent of individuals in a 101 member LQT2 family study by
Kaufman et al.204 and 40% of gene carriers from 10 LQT1 families studied by Chen et
al.54 exhibited QTc values ranging from 400 to 460 ms. Similar observations were made
by Piippo et al. for 34 LQT1 families (739 members)57 and by Vincent et al. in a study of
3 LQT1 families (199 members).257 In the latter study, setting the QTc cutoff at 440 ms
resulted in an 11% misclassification rate for families.
Falsely classifying gene carriers can result in failure to institute risk reduction
measures and, possibly, sudden death, whereas misclassifying noncarriers can result in
unnecessary anxiety and inappropriate treatment. Vincent and co-investigators
recommend setting the QTc cutoff high – 460 ms as applied to general family screening
(in agreement with a 1998 American Heart Association policy statement); 490-500 ms
when screening large numbers of children – so as to avoid falsely identifying numerous
unaffected persons as positive.257-260 Cost-benefit analysis showed that use of fainting as
a criterion for initiating ECG analysis in children (despite the non-specificity of syncope
for LQTS) could reduce the cost per LQTS case detected more than 2-fold.259 The
authors caution against confirmatory use of DNA analysis for children with a pronounced
QTc (i.e., who show strong evidence of being affected based on ECG), as this maneuver
could generate false negatives and lead to treatment avoidance. Of course, when probands
have an identifiable mutation, DNA analysis should be useful for identifying secondary
cases within families.
Typical studies aimed at showing the feasibility of mutation-based risk prediction
in families have involved upwards of 200 families81 and 1000 individuals.256 In the
Netherlands, work-up of family members at 5 cardiogenetic outpatient clinics results in
about 200 families per clinic being seen annually, and has yielded a mean of 3.5
mutation-carrying relatives for each index case.253
Van Langen et al. in the Netherlands used decision analysis on data from 31
unrelated LQTS patients to distinguish between 3 possible genetic screening strategies.80
Screening using the most eligible gene based on reference group prevalences of the
various LQTS genotypes79 correctly identified the mutation in only 45% of the study
population. Screening for the 5 major LQTS genotypes increased clinical sensitivity to
78%, but was “very labour intensive and expensive.” Screening using the most eligible
gene based on individual phenotypic information (personal demographics, past LQTS
history, family data, and ECG characteristics including ST-T segment morphology)
reduced the sensitivity by 8% (to 70%), while labor and cost declined by 80%. The
authors recognized the added complication of patients with compound heterozygous
mutations, but suggested that more prognostic research is needed before screening
patients for more than 1 mutation is conducted. Future decision analyses will need to take
into account the higher than expected frequencies of compound heterozygous mutations
in probands and carrier relatives emerging from various studies.7,8
The Task Force on Sudden Cardiac Death of the European Society of Cardiology
has developed evidence-based recommendations for the various LQTS interventional
modalities.261 For primary prevention of SCD, the weight of evidence supports
restricting competitive sports and strenuous activity, use of beta-blocker therapy, and
careful attention to QT prolonging agents, with implantable cardiac defibrillator (ICD)
use in high risk patients having recurrent syncope. ICD use plus the above principles of
management are warranted for secondary prevention in patients having experienced
aborted cardiac arrest. Evidence and opinion are less consistent for use of pacemakers
and left cardiac sympathetic denervation (Class IIb interventions). Sports requiring
restriction are further detailed in a consensus document developed by the American Heart
Association.262 Genotype-phenotype correlation studies suggest that different forms of
management may be optimal for different LQTS genotypes.263 There may be a
differential response to beta-blocker therapy by genotype.264
Several teams have demonstrated reductions in QT interval length and T-wave
abnormalities in LQT2 patients following intravenous and oral potassium
administration.265,266 Long-term therapy with potassium supplementation and potassiumsparing agents is unable to maintain serum potassium above set levels, however, due to
kidney homeostasis.267 Class Ic sodium channel blockers may counter the gain-offunction abnormality in LQT3,268 but run the risk of creating a pharmacologic Brugada
syndrome phenotype.270 Drug rescue of misfolded ion channel proteins with the use of
protein stabilizing pharmacological chaperones has also been demonstrated, e.g.,
terfenadine (fexofenadine) for certain HERG mutations,270 and mexilitine in the case of
select SCN5A mutations.271 These experimental findings need clinical confirmation –
applicability may be limited to only certain mutation-induced trafficking abnormalities.272
While gene therapy for electrical re-engineering of ventricular tissue has been proposed,
such research has so far focused on atrial fibrillation and the atrioventricular node, and
induction of angiogenesis in ischemic heart tissue.41,273
Prevention of sudden cardiac death based on decedent information
Clinicians and epidemiologists envision an early warning system for at-risk
families. A warning system based on decedent information could be used to alert
surviving family members and relatives having little or no knowledge of arrhythmic
death in the family, reflecting public health’s assurance role.274 In 1999 Ackerman et al.
at the Mayo Clinic used PCR and direct sequencing to perform “molecular autopsy” of
paraffin block-embedded heart tissue from a 17-year-old boy found deceased in bed.
Discovery of a 5-base pair deletion in the KCNQ1 PCR fragment led to the detection of
T-wave abnormalities in the mother following epinephrine challenge.275 Subsequently,
the same group used the molecular approach to detect SCN5A mutations in the frozen
myocardium of 2/93 SIDS cases collected by the Arkansas State Crime Laboratory.276
Analysis by Chugh et al. in Minnesota277 of adult SCD victims with previously
inconclusive autopsies detected HERG mutations in 2/12 (17%) post-mortem tissue
samples. Even in the absence of post-mortem tissue for DNA analysis, aggressive clinical
and molecular genetic screening of relatives of young SCD victims can identify
unsuspected carriers of LQTS gene mutations.278 In the future, these developments will
confront practitioners with new types of ethical and psychosocial dilemmas.279 Part of
the challenge lies in balancing the ethical rules embodied in state public health privacy
laws and HIPAA with needed care for at-risk families.
Translation of study results and provider education
Molecular genetic and large-scale study results require translation into a form
usable by health care providers and public health practitioners. In a 2002 survey of 581
physicians in Northern Israel, only 31% of pediatricians and 54% of family practitioners
realized that the prokinetic drug cisapride (currently removed from the U.S. market) can
cause prolongation of the QT interval.280 Even more significantly, a 12-country survey
disclosed that < 50% of cardiologists and < 40% of noncardiologist physicians calculate
the QTc correctly.281 Public health and health care institutions have a responsibility to
assure a competent workforce able to use genetic information to promote health and
prevent disease.274
Identification of novel LQTS alleles
Fifty-nine percent of the mutations reported by Tester et al. in their mutational
screening survey of 541 LQTS patients were novel.59 The list of alleles falling within
LQTS coding regions continues to expand. An emerging area of interest is also the
discovery of noncoding regions that may be responsible for LQTS, such as the HERG
T1945+6C intronic mutation recently identified by Zhang et al. as a disease-causing
alteration.282 Polymorphisms in noncoding regions may also contribute to gene
regulation.90 Researchers may find mutations in other ion channel genes (e.g., analogues
of K+ channel genes heavily studied in other species, Ca2+ channel gene variants) and in
other proteins (subserving transport, anchoring, and phosphorylation) that could interact
with the known LQTS genotypes or constitute new genotypes.283,284 Future gene
discoveries will require tandem efforts involving in vitro investigation of mutant
constructs and genetic epidemiology of populations, with genotyping of large numbers of
carefully phenotyped at-risk individuals and controls.90
Prediction of disease severity
The end goal of gene identification is risk assessment for individuals, families,
and populations. Clinicians currently have a rough idea of the difference in lethality of
cardiac events between the various LQTS genotypes.94 Some protein domains29,62,213
may present with a more severe phenotype. Though various technical criteria exist to
decide whether a given mutation is pathogenic88,90,91,247,285-287 experts are still in the
process of resolving how to predict whether a given mutation will present as mild or
more severe.9 Further, practitioners are far from being able to assign adverse or favorable
prognoses on the basis of genotype or specific mutation.288 Continued investigation of
the functional effects of pathogenic mutations in vitro, and comparison of affected and
control populations in different countries and kindreds is needed.9
Elucidation of the genetic basis of modifying pathways
The elucidation of polymorphisms involved in other signaling pathways and of
modifying factors such as hormonal influences are areas requiring further research.
Members of a workshop on SCD sponsored by the National Heart, Lung, and Blood
Institute viewed the investigation of pathways modulating local and systemic responses
to autonomic transmitters as a priority.289 Polymorphic variation in genes that influence
sympathetic tone, such as those encoding beta1 and beta2-adrenergic receptors, is in need
of further investigation.290 Of continued concern are the proximal mechanisms
responsible for arrhythmia initiation and the transition from stable tachyarrhythmias to
fibrillation in SCD.291
LQTS as a paradigm for other areas of investigation
LQTS serves as a paradigmatic condition in arrhythmia research and genetic
research in general. What is being learned about the multifold pathogenetic mechanisms
behind LQTS can be applied to other channelopathies, including periodic paralyses,
episodic myotonias, and ion channel epilepsies.292-294 LQTS research bridges phenomena
at the molecular genetic, tissue, and systemic levels.5 The LQTS family of disorders is
highly pleiomorphic yet orderly, serving as a conceptual scaffolding for other complex
genetic conditions.
Clinical practice and public health share the goals of primary and secondary
prevention of LQTS-related sudden cardiac death. Researchers have made considerable
strides in the identification of LQTS genes and their variant forms. Investigators and
practitioners are especially aware of the complexity of accurate diagnosis and prognosis
in this area. Despite uncertainties, action must nonetheless be taken for at-risk patients,
family members and groups, since LQTS is potentially fatal. This review of LQTS ends
on a positive note, since the exploration of significant disease variants and the
determination of socially sensitive policy are moving hand-in-hand as commercial
screening becomes a real possibility.
Note added in proof: Recently a paper has been published reporting the existence
of nonprivate mutations in ~ 50% of LQTS probands, a finding that may help to
streamline genotypic screening. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic
testing in the long QT syndrome: development and validation of an efficient approach to
genotyping in clinical practice. JAMA 2005;294:2975-80.
Informational internet sites: Information centers
Office of Genomics and Disease Prevention (OGDP), Centers for Disease Control
and Prevention:
European Long QT Syndrome Information Center:
Drugs That Prolong the QT Interval and/or Induce Torsades de Pointes (hosted by
Raymond L. Woosley, MD, PhD):
LQTS registries
Cardiac Arrhythmias Research and Education (CARE) Foundation Long QT
Russian National Registry for Patients with Long QT Syndrome:
Genetic databases
“Gene Connection for the Heart” LQTS Database, European Society of
Cardiology Study Group on Molecular Basis of Arrhythmias, Last updated 5/20/05:
“Long QT Syndrome Database,” Human Genome Organisation (HUGO), Last
updated 5/03:
Online Mendelian Inheritance in Man (OMIM):
Statens Serum Institute, Copenhagen, Denmark:
Boston University School of Medicine Center for Human Genetics DNA
Diagnostics Laboratory:
Genaissance Pharmaceuticals FAMILION Cardiac Ion Channel Mutations
Consumers and professionals
Cardiac Arrhythmias Research and Education (CARE) Foundation:
Sudden Arrhythmia Death Syndromes Foundation:
Long QT Syndrome Support Center:
Production of this HuGE Review was supported by the Michigan Center for
Genomics and Public Health, under a Centers for Genomics and Public Health grant from
the Centers for Disease Control and Prevention and the Association for Schools of Public
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