A Recessive Variant of the Romano-Ward
Long-QT Syndrome?
Silvia G. Priori, MD, PhD; Peter J. Schwartz, MD; Carlo Napolitano, MD; Laura Bianchi, PhD;
Adrienne Dennis, PhD; Maurizio De Fusco, BS; Arthur M. Brown, MD, PhD; Giorgio Casari, PhD
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Background—The congenital long-QT syndrome (LQTS) is a genetically heterogeneous disease characterized by
prolonged ventricular repolarization and life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac
potassium channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a dominant trait, and the
Jervell and Lange-Nielsen syndrome, inherited as an autosomal recessive trait.
Methods and Results—A consanguineous family with the clinical phenotype of LQTS was screened for mutations in the
KVLQT1 gene. Complementary RNAs for injection into Xenopus oocytes were prepared, and currents were recorded
with the double microelectrode technique. A homozygous missense mutation, leading to an alanine-to-threonine
substitution at the beginning of the pore domain of the KVLQT1 channel, was found in the proband, a 9-year-old boy
with normal hearing, a prolonged QT interval, and syncopal episodes during physical exercise. The parents of the
proband were heterozygous for the mutation and had a normal QT interval. The functional evaluation of the mutant
channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster activation rate
consistent with a mild mutation likely to require homozygosity to manifest the phenotype.
Conclusions—These findings provide the first evidence for a recessive form of the Romano-Ward long-QT syndrome and
indicate that homozygous mutations on KVLQT1 do not invariably produce the Jervell and Lange-Nielsen syndrome.
The implications of this observation prompt a reconsideration of the penetrance of different mutations responsible for
LQTS and suggest that mild mutations in LQTS genes may be present among the general population and may predispose
to drug-induced ventricular arrhythmias. (Circulation. 1998;97:2420-2425.)
Key Words: arrhythmia n genetics n molecular biology n torsade de pointes n death, sudden
T
he congenital long-QT syndrome (LQTS) is a disease
characterized by prolongation of ventricular repolarization and by the occurrence, usually during emotional or
physical stress, of life-threatening arrhythmias that lead to
sudden death in most of the symptomatic and untreated
patients.1– 4 Mutations in ion channel genes involved in the
control of ventricular repolarization have been shown to
cause LQTS.5–7
Since 1975,1 the acronym LQTS has included two variant
forms of the disease with a similar cardiac phenotype: the rare
Jervell and Lange-Nielsen syndrome, with congenital sensorineural deafness and ventricular repolarization abnormalities, and the more common Romano-Ward syndrome, with
only cardiac manifestations. The pattern of inheritance of
LQTS has always been regarded as firmly established:
autosomal dominant for Romano-Ward syndrome and autosomal recessive for Jervell and Lange-Nielsen syndrome.8
Recently, concordant evidence from two laboratories9,10 demonstrated that LQT1 (the Romano-Ward syndrome form
linked to chromosome 11) and Jervell and Lange-Nielsen
syndrome are allelic diseases caused by mutations in the
KVLQT1 gene. The KVLQT1 gene product coassembles with
minK and constitutes the cardiac potassium channel conducting the IKs current, the slow component of the delayed
rectifier current, IK.11,12
In 1980, contrary to current views, we hypothesized that
LQTS might include patients without prolongation of the QT
interval.13 This was proved correct by the evidence that
cardiac arrest occurs in 4% of LQTS family members with a
normal QT14 and later by the identification of KVLQT1 gene
mutation carriers with a normal QT interval.15
We have now hypothesized that the spectrum of the genetic
transmission of the disease might be larger than expected and
might include mild mutations for the Romano-Ward syndrome that would become manifest only when a “double
dose,” the homozygous state, is present. This would point to
the possible presence of an extreme degree of incomplete
penetrance in LQTS and would also imply the previously
Received October 2, 1997; revision received January 29, 1998; accepted February 10, 1998.
From the Telethon Institute of Genetics and Medicine (TIGEM), San Raffaele Biomedical Science Park, Milan (S.G.P., C.N., M.D.F., G.C.); the
Molecular Cardiology and Electrophysiology Laboratory, Fondazione “S. Maugeri” IRCCS, Pavia (S.G.P., C.N.); the Department of Cardiology,
University of Pavia and Policlinico S. Matteo IRCCS, Pavia (S.G.P., P.J.S.); the Centro di Fisiologia Clinica e Ipertensione, University of Milan, Ospedale
Maggiore IRCCS, Milan (P.J.S., C.N.), Italy; and the Rammelkamp Research Center, Case Western Reserve University, Cleveland, Ohio (L.B., A.D.,
A.M.B.).
Correspondence to Giorgio Casari, PhD, Research Unit Coordinator, Telethon Institute of Genetics and Medicine, S. Raffaele Biomedical Science Park,
Via Olgettina 58, 20132 Milan, Italy. E-mail [email protected]
© 1998 American Heart Association, Inc.
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Priori et al
June 23, 1998
2421
Figure 1. Pedigree structure of consanguineous
Romano-Ward syndrome family. Direct sequence
determinations (from left, ACGT) are shown below
parents (IV-1 and IV-2), proband (V-4), and his
unaffected brother (V-2). Homozygous G/A transition causing missense A300T is in bold type. Gray
symbols denote sudden death.
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unsuspected existence of a “recessive form” of RomanoWard syndrome. Should this hypothesis be correct, there
would be significant implications for establishing the frequency of LQTS mutation carriers in the general population,
which could be higher than generally expected. Also, the
existence of heterozygous mild mutations on KVLQT1, which
would nonetheless be highly sensitive to any drug that blocks
potassium currents, would be relevant to the major clinical
problem of drug-induced torsade de pointes and of the
acquired LQTS.4 Here, we present the evidence for the
presence of a homozygous KVLQT1 mutation in a RomanoWard syndrome family.
Methods
Mutation Analysis
DNA was extracted from peripheral blood lymphocytes by
standard procedures.16 Primer pairs for LQTS5,6 were used to
amplify exons of KVLQT1 gene, and [a-32P]dCTP was added to
the polymerase chain reaction (PCR) mix to obtain radiolabeled
fragments. Single-strand conformational polymorphism (SSCP)
analysis was performed on amplified genomic DNA.17 Two to 4
mL of each PCR product was mixed with loading dye (98%
formamide, 10 mmol/L EDTA, 0.025% xylene cyanol, and
0.025% bromophenol blue) in a final volume of 8 mL. The
samples were then denatured for 10 minutes at 95°C, chilled on
ice, and loaded on a native 6% acrylamide (62.5:1 acrylamide:bisacrylamide) gel containing 10% glycerol. The gel was run at room
temperature at 35 W for 4 hours. Samples resulting in mobility
shifts were directly sequenced or subcloned into pBlueScript
SK2 (Stratagene) and sequenced on both strands by use of the
Sequenase version 2.0 DNA Sequencing Kit (USB). The multiple
sequence comparison was performed by the GCG Wisconsin
Sequence Analysis Package, version 8.1, Genetics Computers
Group, Inc.
Mutagenesis and Expression
KVLQT1 mutant construct was prepared by overlap extension at the
mutation site by use of sequential PCR.18 The resulting PCR
fragments were subcloned into the pCR2.1 for sequence verification
and amplification. Plasmids containing the correct mutations were
then digested with NcoI/BglII, and the resulting 550-bp fragments
were subcloned into gel-purified NcoI/BglII– digested KVLQT1-SP6
vector. Complementary RNAs for injection into Xenopus oocytes
were prepared with the mMESSAGE mMACHINE kit (Ambion)
using SP6 RNA polymerase after linearization of the plasmids with
EcoRI. Each cRNA was dissolved in 0.1 mol/L KCl, and its size was
verified and concentration estimated by formaldehyde-agarose gel
electrophoresis. All cRNAs were diluted to the final desired concentration in a constant volume of 46 nL before oocyte injection.
Currents were recorded at room temperature ('21°C) 3 to 5 days
after the injection. The conventional double-microelectrode technique was applied with an OC-725B Warner Institute amplifier.
Electrodes were filled with 3 mol/L KCl and had a resistance of 5 to
10 MV. The solution used to perfuse the oocytes contained
(in mmol/L) N-methyl-D-glucamine 120, KOH 2.5, MgCl2 2, methanesulfonic acid 120, and HEPES 10 (pH 7.4 with Tris-OH). Data
acquisition and analysis were performed with the pClamp suite of
programs. Data were filtered at 0.2 kHz and digitized at 0.7 kHz.
Results
Phenotypic Characterization
A 9-year-old boy was referred to our attention in 1981 after
a first syncopal episode with loss of urine during physical
exercise. He was the offspring of a consanguineous marriage
of second-degree cousins (see pedigree in Figure 1). A
complete medical evaluation was unremarkable, the only
abnormality being a prolongation of the QT interval (QTc 470
ms in lead V2) (Figure 2). Two brothers of the proband (V-1
and V-3) died suddenly at the ages of 3 and 9 years while
sleeping and while swimming, respectively; no ECGs were
available. A third brother had a normal QT interval (QTc 440
ms) and no history of cardiac symptoms (Figure 2). The boy
was diagnosed as affected by the Romano-Ward type of
LQTS2 with a score of 5.5 (4 points5high probability of
LQTS).19 His mother and father had normal ECGs, negative
cardiac histories, and diagnostic scores of 0.5 (,1 point5low
probability of LQTS). Their QTcs were at the upper limits of
normal values (450 and 440 ms) both at rest (Figure 2) and
during sinus tachycardia. The QT shortening during increased
heart rate in the affected son and in the two parents was
within the limits observed for normal individuals, limits that
differ only slightly from those observed among LQT1 patients20,21; moreover, no repolarization abnormality suggestive
of LQTS became evident during tachycardia in the heterozygous parents. The proband’s ECG showed the broad-based,
tall T waves often encountered in LQT1 patients,22 whereas
2422
Recessive Romano-Ward Long-QT Syndrome
individuals. Thus, the hearing loss phenotype is absent in the
proband, who shows the cardiac phenotype of LQTS. These
findings are consistent with the identification of the first
Romano-Ward variant of LQTS inherited as a recessive trait.
Molecular Screening
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Figure 2. ECG recording in patients IV-1 (A300T heterozygous
father), IV-2 (A300T heterozygous mother), V-2 (homozygous
wild-type son), and V-4 (homozygous A300T son). Leads DII, V2,
and V4 are presented. QTc is prolonged in the proband, whereas
QTc is within normal values both in heterozygous carriers (parents) and in unaffected brother.
the T wave morphologies of both parents were completely
normal. The proband has been treated with b-blockers and,
16 years later, remains asymptomatic.
To exclude the possibility of a “forme fruste” of the Jervell
and Lange-Nielsen syndrome, an audiogram was performed
in the proband (V-4) and the unaffected brother (V-2) to
verify a possible hearing difference. The audiogram assessed
sound frequencies between 250 and 11 000 Hz. The curves of
the proband and his brother were superimposable and bilaterally identical, showing a flat profile between 250 and 3000
Hz; the curve slightly declined for sound frequencies .3000
Hz (Figure 3). The response was considered optimal in both
An abnormal migration pattern was identified in one fragment of the KVLQT1 gene– encompassing exon.5 None of the
100 control individuals presented the same SSCP pattern.
Sequence analysis revealed a homozygous mutation leading
to a single-residue substitution that resulted in an amino acid
change for alanine to threonine at position 300 (A300T). This
amino acid lies at the beginning of the pore region of the
predicted topology of KVLQT1.23 As shown in Figure 4, the
A300 is conserved in homologous proteins deriving from
such distant species as human, mouse, frog, and nematode6,11,12,24 and is positioned at the beginning of the pore, the
most conserved domain. The amino acid change, replacing a
nonpolar alanine with a polar hydrophilic threonine, is likely
to alter this functionally important part of the molecule. At
the same time, this replacement must affect the function of
the protein only mildly, because the long-QT phenotype is
absent in heterozygous carriers. Both consanguineous parents
of the proband are heterozygous for the A300T mutation,
whereas the healthy brother inherited the two wild-type
alleles (Figure 1).
Expression of the Mutant Channel cRNA
After coinjection of wild-type KVLQT1 and minK25 mRNAs,
depolarizing voltage steps elicited slowly activating and
deactivating currents typical of the IKs current recorded after
coinjection in Xenopus oocytes and CHO, Sf9, COS,11,12 and
HEK293 cells.23 The peak current recorded at 40 mV after
coinjection of the mutant A300T-KVLQT1 and minK was
25% wild type and was significantly greater (P,0.05) than
the current elicited in oocytes injected with minK alone. The
activation of A300T KVLQT11minK had a tau51.29 (0.02
seconds at 140 mV, n55). The values were faster than the
wt-KVLQT11minK, 1.88 (0.05 seconds at 140 mV; n55),
and resembled the faster rate of activation observed after
expression of KVLQT1 alone.11 In addition, the isochronal
activation-voltage curves of A300T KVLQT11minK differed from the wt-KVLQT11minK in that the midpoint was
shifted to more negative potentials by .20 mV (Figure 5).
Therefore, these electrophysiological characteristics of the
mutated isoform are compatible with the mild effect expected
for a recessive mutation.
Discussion
Figure 3. Audiometric test performed in proband. Audiogram
assessed perception of sound frequencies between 250 and
11 000 Hz. Curves were normal and bilaterally identical, showing flat profile between 250 and 3000 Hz; curve slightly declined
for sound frequencies .3000 Hz.
The present report provides the first evidence for a RomanoWard syndrome in which the cardiac phenotype is not
manifest in heterozygous individuals, thus suggesting the
existence of a recessive form of the Romano-Ward long-QT
syndrome. Since its first description26,27 and until now,8 the
Romano-Ward syndrome has always been considered an
autosomal dominant disease. Our finding of a mutation on the
KVLQT1 gene, which produces the cardiac phenotype of
Romano-Ward syndrome only in the homozygous form, is a
sharp departure from previous reports.6,28 Indeed, consistent
Priori et al
June 23, 1998
2423
Figure 4. Multiple sequence alignment analysis of KVLQT1 and homologous proteins: hKVLQT1, human6; mKVLQT1, mouse12; rKVLQT1, rat (GenBank RNU92655); xKVLQT1, Xenopus laevis11; ce25b8 and cem60, Caenorhabditis elegans24; and HNSPC, a predicted K
channel cDNA from a human neuroblastoma cell line.37 Black line above sequence alignment denotes putative pore domain. Amino
acid identities are boxed. Asterisk marks mutated A300.
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with dominant diseases, the reported mutations on KVLQT1
were all capable of producing the LQTS cardiac phenotype in
the heterozygous carriers of the mutations. The present
finding demonstrates that homozygous mutations on KVLQT1 do not invariably produce the Jervell and LangeNielsen syndrome.9,10 The implications of this observation are
relevant for the definition of the variable phenotypes associated with mutations in the KVLQT1 gene and for reconsidering the penetrance of different mutations responsible for
LQTS. Finally, these observations offer new insights on the
puzzling and significant problem of drug-induced long-QT
syndrome.
A Romano-Ward Family Without
Dominant Inheritance
In this family, the A300T mutation was associated with the
cardiac phenotype of LQTS only in the homozygous proband.
Both parents are heterozygous carriers of the mutation and
had a normal phenotype. The previous description of a family
with QT prolongation and only partial hearing loss 29
prompted the performance of an audiogram test on the
proband that, being completely normal, ruled out even a mild
form of the Jervell and Lange-Nielsen syndrome. The cardiac
phenotype characterized by QT prolongation and arrhythmias
of both Romano-Ward and Jervell and Lange-Nielsen LQTS
is currently considered to be inherited as a dominant trait.10
Mutation-Specific Pattern of Inheritance in Ion
Channel Diseases
Molecular diagnosis has revealed an unsuspected level of
complexity, proving that penetrance may be variable and that
different mutations produce different clinical phenotypes.
Indeed, this has already been shown for other diseases, such
as the Thomsen’s and Becker’s types of myotonia,30 the
Figure 5. Functional expression in Xenopus oocytes of wt-KVLQT11minK and A300T1minK. A, Examples of current traces obtained
from oocytes injected with wt-KVLQT1 (500 ng/mL) or A300T (500 ng/mL)1minK (100 ng/mL). Currents were elicited by depolarizing
pulses from 240 to 170 mV in 10-mV steps, starting from a holding potential of 280 mV; return potential was 260 mV. Dotted lines
indicate zero current. Bottom, Mean current amplitudes elicited at 140 mV from a holding potential of 280 mV for wt-KVLQT11minK
(n57) and A300T1minK (n59). A300T1minK mutant mean current was significantly different (P,0.05, Student’s t test) from minK mean
current. B, Normalized isochronal activation curves obtained by voltage protocol described in A. Isochronal (t52700 ms) activation
curves were averaged for wt-KVLQT11minK (solid circles; n510) and for A300T1minK (open circles; n510). Experimental data were
fitted with the Maxwell-Boltzmann equation, 1/[11exp(V2V1/2)/k], which gave the following V1/2 and slope factor values: V1/2532.8 mV,
slope514.4 mV for wt-KVLQT11minK; and V1/2513.9 mV, slope519.1 mV for A300T1minK. Values are mean6SEM.
2424
Recessive Romano-Ward Long-QT Syndrome
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former dominant and the latter recessive. They both are
actually caused by different mutations on the same gene, the
skeletal muscle chloride channel CLCN1. A further example
is the case of Liddle’s syndrome, a dominant disease caused
by mutations in the b-subunit of the epithelial sodium
channel SCNN1B that result in a gain of function with
increased sodium reabsorption.31 However, pseudohypoaldosteronism, a recessive disease, is caused by different mutations of the same SCNN1B gene leading to a loss of function
of the gene product.32 All these examples belong to ion
channel diseases in which, in remarkable analogy to what we
report here for LQTS, different mutations on the same genes
determine quite different phenotypes.
The evidence provided here questions the appropriateness
of the traditional definition of the two forms of LQTS:
Romano-Ward, with cardiac phenotype and dominant pattern
of inheritance, and Jervell and Lange-Nielsen, with cardiac
and auditory phenotypes associated with a recessive pattern
of inheritance. Splawski et al10 recently proposed that the
cardiac phenotype is inherited as a dominant trait and the
auditory phenotype, deafness, is inherited as a recessive trait.
This phenotypic difference between heterozygous and homozygous carriers of the same mutation is probably due to a
different sensitivity of the affected districts: the marginal
cells of the stria vascularis producing the endolymph in the
inner ear9,33 are likely to be less sensitive to partial KVLQT1
inactivation than the cardiac tissue. However, the dominant
pattern of inheritance of long-QT syndrome reflects the
dominant negative effect of the KVLQT1 mutated subunit
onto the hetero-oligomeric complexes formed by KVLQT1
and minK,11,12 which produces a loss of function of the
complex. Our data indicate that the cardiac phenotype also
may become manifest only in homozygous individuals.
From a strictly technical point of view, the appearance of
the clinical phenotype in homozygous but not in heterozygous carriers of a mutation fits the classic definition of a
“recessive” pattern of inheritance. This concept is further
strengthened by the consanguineity of the parents of the
proband as observed in the family we describe here. However, the situation here is more complex, and a few additional
considerations are in order. The number of gene carriers not
presenting the disease phenotype is clearly larger than expected as a consequence of the incomplete penetrance of
some of the LQTS mutations. The one described here might
represent an extreme case of incomplete penetrance of a
dominant disease producing a recessive pattern of
inheritance.
Our data do not allow a definitive answer. We favor the
interpretation of a recessive variant because of the demonstration of the very modest in vitro electrophysiological
consequence of the A300T mutation. However, at present it is
not possible to estimate the risk of the proband to transmit the
disease to a heterozygous offspring. Even though the two
heterozygous individuals with the A300T mutation do not
present the LQTS phenotype, we cannot exclude the possibility that a heterozygous individual may show some of the
clinical signs of the disease.
We hypothesize that at least some of what are currently
considered “sporadic cases” could be affected by a recessive
form of Romano-Ward syndrome as compound heterozygotes. This possibility could explain part of the variable
penetrance observed in some families.
Functional Expression of the Mutated
KVLQT1 Gene
The A300T mutation clearly reduced the IKs current. Two
other point mutations in KVLQT1, which we found to be
responsible for cases of dominantly inherited LQTS, were
also tested and showed significantly greater reductions in IKs
current (A.M.B., unpublished data, 1997). The present mutation not only expressed a significant hyperpolarizing shift of
the activation voltage curve but also had a faster activation,
which is likely to attenuate the reduction in outward K1
current at repolarizing potentials. These three characteristics,
a less severe reduction in total current, a hyperpolarizing shift
in activation, and a faster activation rate, render the A300T a
mild mutation and may explain why homozygosity is required for manifestation of the cardiac phenotype.
Implications for the Acquired LQTS
The previously unsuspected evidence that the most frequent
type of LQTS, the Romano-Ward syndrome, can depend on
mutations that remain silent when present on only one allele
suggests that the number of LQTS gene carriers may by far
exceed previous considerations. The findings presented here
have implications that extend beyond the congenital LQTS
and involve genetically transmitted dominant diseases and the
acquired long-QT syndrome. One can indeed foresee that the
extension of molecular screening will demonstrate that a
significant number of apparently normal individuals carry
“dormant” mutations that produce a clinical phenotype either
when they are present on both alleles or whenever they
interact with specific external factors, eg, drugs that prolong
repolarization.
It has been suspected34 that the drug-induced LQTS might
have been a “forme fruste” of congenital LQTS, but the
molecular tools to test this hypothesis were not available. We
recently obtained the first evidence for typical drug-induced
torsade de pointes in a 77-year-old woman who was taking
cisapride, a prokinetic agent that blocks IKr,35 and who was
found to have a mutation on KVLQT1.36 These data confirm
the concurrent deleterious interaction of a genetically defective repolarization and a potassium channel– blocking agent.
Conclusions
The present report provides the first evidence of the existence
of a recessive Romano-Ward syndrome. LQTS caused by
KVLQT1 mutations presents substantial phenotypic heterogeneity. It may be associated with a cardiac phenotype inherited
as autosomal dominant, with a cardiac phenotype inherited as
autosomal recessive, and with a cardioauditory phenotype
inherited as a recessive trait. It is now more accurate to define
the Romano-Ward syndrome as showing the pure cardiac
phenotype of LQTS, independently of its pattern of inheritance, which appears to be a mutation-dependent feature.
Furthermore, the reported findings induce us to reconsider the
penetrance of different mutations responsible for LQTS and
also suggest that mild mutations in LQTS genes may be
Priori et al
present in the general population and may predispose to
drug-induced life-threatening ventricular arrhythmias.
Acknowledgments
This work was supported by the Italian Telethon Foundation
(TIGEM, grants 748 and 1058) and by EC grant BMH4-CT96-0028.
We thank all the family members for their participation in this study.
We thank Pinuccia De Tomasi for secretarial support.
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A Recessive Variant of the Romano-Ward Long-QT Syndrome?
Silvia G. Priori, Peter J. Schwartz, Carlo Napolitano, Laura Bianchi, Adrienne Dennis, Maurizio
De Fusco, Arthur M. Brown and Giorgio Casari
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Circulation. 1998;97:2420-2425
doi: 10.1161/01.CIR.97.24.2420
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