(Circulation. 1999;99:529-533.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Low Penetrance in the Long-QT Syndrome
Clinical Impact
From the Molecular Cardiology and Electrophysiology Laboratory, Fondazione "Salvatore Maugeri" IRCCS, Pavia (S.G.P., C.N.); the Department of Cardiology, University of Pavia and Policlinico S. Matteo IRCCS, Pavia (P.J.S.); and the Centro di Fisiologia Clinica e Ipertensione, University of Milan, Ospedale Maggiore IRCCS, Milan (C.N.), Italy.
Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology and Electrophysiology Laboratory, Fondazione "S. Maugeri" IRCCS, Via Ferrata, 8, 27100 Pavia, Italy. E-mail spriori{at}fsm.it
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Abstract |
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Background—It is still currently held that most patients affected by the long-QT syndrome (LQTS) show QT interval prolongation or clinical symptoms. This is reflected by the assumption in linkage studies of a penetrance of 90%. We had previously suggested that a larger-than-anticipated number of LQTS patients might be affected without showing clinical signs. We have now exploited the availability of molecular diagnosis to test this hypothesis.
Methods and Results—We identified 9 families with "sporadic" cases of LQTS, ie, families in which, besides the proband, none of the family members had clinical signs of the disease. Mutation screening by conventional single-strand conformational polymorphism and sequencing was performed on DNA of probands and family members to identify mutation carriers. Of 46 family members considered on clinical grounds to be nonaffected, 15 (33%) were found instead to be gene carriers. Penetrance was found to be 25%. In these families, conventional clinical diagnostic criteria had a sensitivity of only 38% in correctly identifying carriers of the genetic defect.
Conclusions—This study demonstrates that in some families, LQTS may appear with a very low penetrance, a finding with multiple clinical implications. The family members considered to be normal and found to be silent gene carriers are unexpectedly at risk of generating affected offspring and also of developing torsade de pointes if exposed to either cardiac or noncardiac drugs that block potassium channels. It is no longer acceptable to exclude LQTS among family members of definitely affected patients on purely clinical grounds. Conversely, it now appears appropriate to perform molecular screening in all family members of genotyped patients.
Key Words: arrhythmia • genetics • molecular biology • torsade de pointes • sudden death
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Introduction |
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Several of the genes responsible for the long-QT syndrome (LQTS)1 2 3 have been identified.4 5 6 7 Novel possibilities exist not only to understand how genetically mediated alterations in the ionic control of repolarization affect the manifestations of this often lethal disease but also to define its elusive epidemiology. The latter point derives from the ability to combine clinical and molecular diagnosis when studying potentially affected families.8
For many years, it was taken for granted that each patient affected by LQTS had a prolonged QT interval; this implied a penetrance of or close to 100%. Penetrance represents the probability for an individual with an affected genotype to manifest the clinical signs of the disease, and it has important implications for clinical management. The most reliable approach to define penetrance is to perform mutation screening in family members of affected and genotyped individuals.
Even now, most laboratories, when performing linkage
analysis,9 10 11 12 assume that the disease has a
penetrance 
90%. This concept was challenged as early as 1980 by
Schwartz,13 who proposed, on theoretical grounds, that the
spectrum of the disease might have been larger than previously thought
and that it might have included patients with a normal QT interval.
This hypothesis implied that the penetrance of LQTS in some families
might have been well below the traditional 90%; this was supported
first by the evidence that 6% of LQTS family members with a normal QT
interval had syncope or cardiac arrest14 and later by the
evidence that among the gene carriers of 3 LQT1 families, a few (6%)
had a normal QT interval.15
To definitely prove or dismiss this hypothesis and to truly estimate the range of penetrance in LQTS, we selected kindreds in which only the proband was diagnosed clinically as being affected by LQTS. On purely clinical grounds, these patients are traditionally defined as "sporadic cases." They may actually represent either "de novo" mutations or instances of truly low penetrance. Accordingly, to discriminate between these possibilities, we performed mutation screening in all available family members to identify potential silent gene carriers.
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Methods |
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Study Population
Among the population of LQTS patients followed by our group since 1975, we selected those Italian families for which we had first-hand information spanning 3 generations. There were 82 such families. Among these 82 families, there were 32 (39%) in which only 1 member was clinically affected, thus fulfilling the description of sporadic cases. The probands of 9 of these families were successfully genotyped, thus making possible the molecular diagnosis of the available family members.
Nine genotyped probands without clinically affected family
members entered the study. The living family members (n=52) were
offered the opportunity to enter the study. Four individuals live in
Canada and were not interested, and 2 other subjects refused to
participate because they were afraid of the potential diagnosis,
whereas 46 accepted and are included in the present
analysis. LQTS-affected individuals were defined on the basis
of current diagnostic criteria,9 16 including
a QTc >470 ms in asymptomatic individuals and a QTc >440
ms for males and >460 ms for females associated with 1 of the
following: (1) stress-related syncopal episodes, (2) documented torsade
de pointes, or (3) family history of early (<35 years of age) sudden
cardiac death. Peripheral venous blood (5 mL), two 12-lead
ECGs with >4 QRS complexes in each lead, and a detailed family and
personal history were obtained for each family member. Each individual
was offered the option to refuse testing. Family 5 has been
presented elsewhere.17
Mutation Analysis
DNA was extracted from peripheral blood lymphocytes.
Synthetic oligonucleotides were used to amplify genomic
DNA by polymerase chain reaction. For each reaction, we used 100 ng of
genomic DNA. Published primer pairs5 6 were used to
amplify fragments of HERG and KvLQT1.
Identification of mutations was performed by a standard single-strand
conformational polymorphism and sequencing protocols performed on
DNA of probands, family members, and 100 control individuals, as
previously described.17 All mutations were
demonstrated to be unique to the patients and were absent in control
individuals.
Mutated amino acids are numbered from the starting methionine according to clones AF 000571 and U04270.
Statistical Analysis
QTc values between probands and family members who were or were
not gene carriers were compared by ANOVA and Scheffé's post hoc
analysis; statistical significance was accepted for values of
P<0.05.
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Results |
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Study Population
Among the 9 probands (5 females), 6 (66%) were symptomatic for syncopal episodes. The mean age at first episode was 21±21 years (range, 8 to 62 years; median, 10.5 years). Mean QTc in lead II was 504±48 ms. Two asymptomatic probands were diagnosed because of prolongation of QT interval at routine investigation (473 and 540 ms, respectively), and the third was diagnosed after a cardiological examination prompted by her 13-year-old brother's sudden death while swimming. Genotyping revealed that 5 probands had missense mutations in the HERG gene resulting in an amino acid substitution and 4 had missense mutations in the KvLQT1 gene (Table 1
).
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Forty-six family members entered the study. All of them had been considered not to be affected by LQTS on the basis of the traditional single 12-lead ECG recording performed by the cardiologist in charge of the family. At entry into the study, they all underwent 3 ECGs on separate days, and blood samples were obtained for mutation screening.
Molecular Versus Clinical Diagnosis
We were in the position of comparing clinical and molecular
diagnoses. In 55 individuals, molecular diagnosis revealed that 9
probands (mean age, 23±17 years) and 15 family members (43±15 years)
were mutation carriers (total, 24 individuals, 12 females). The ECG
criteria currently used in linkage studies10 (see Methods)
correctly identified all probands as affected but missed all gene
carriers among family members. The morphology of the T wave in family
members was normal and did not present notches18 in
any of the 12 leads. The distribution of QTc duration in lead II
(Figure 1) as well as the
diagnostic criteria proposed by Schwartz et
al16 showed overlap between family members who were and
were not gene carriers. All 9 probands and none of the family members
had a score 4 (high probability of LQTS); all 9 probands and 4 gene
carrier family members had a score 2 (intermediate probability of
LQTS). Therefore, the clinical diagnostic criteria
performed as well as the ECG criteria (sensitivity, 38%; specificity,
100%) when a score 4 was used for the identification of "affected
individuals." By contrast, less strict criteria (score 2) increased
sensitivity (54%) at the expense of specificity (90%) (Table 2).
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The availability of molecular diagnosis proved that the traditional
clinical approach would have missed the identification of at least 11
gene carriers who had no obvious signs of LQTS (Figure 2) and would have incorrectly labeled as
affected 3 healthy individuals.
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Penetrance of LQTS
The parents of 4 probands were not carriers for the mutation, and
paternity was confirmed by 7 highly polymorphic markers (not
shown). These individuals were therefore considered to be carrying de
novo mutations. By contrast, in the remaining 5 families, we identified
at least 1 gene carrier among family members. This made it possible to
calculate "penetrance," defined as the ratio between patients with
the clinical phenotype (QT prolongation according to the
above-mentioned criteria) and the total number of family member
carriers of the mutation identified in the proband. Average penetrance
in these families was found to be 25%, because, of a total of 20 gene
carriers, 5 patients had clinical signs of the disease. The penetrance
in family 3 (Figure 2
), with the A561V mutation in
HERG, is 25%; interestingly, other families with the same
mutation have a complete penetrance.19
The analysis of the family history of each proband allowed the identification of 3 individuals who died suddenly at the age of 12, 13, and 14 years, respectively; 2 were within the same family. On the basis of the reasonable assumption that these victims of sudden death also were gene carriers who manifested the disease in the most tragic way, we recalculated the penetrance and obtained an average value of 35%, because, of a total of 23 gene carriers, there were 8 clinically affected individuals. The penetrance for each family was 33%, 33%, 25%, 14%, and 33% when the premature sudden deaths were not included, and 33%, 33%, 25%, 25%, and 60% when they were.
Asymptomatic gene carriers were present among both
upstream and downstream generations with respect to the proband. Within
the same generation, or among siblings, carriers of the same mutation
had no concordance of phenotype (Figure 3).
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Discussion |
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Contrary to current assumptions, the present study demonstrates that LQTS may appear in some families with an extremely low penetrance. This finding has implications for the understanding of the disease, for its diagnosis, and for its clinical management.
From Hypothesis to Evidence
In 1980, Schwartz proposed that the spectrum of LQTS might have
been much larger than expected at that time and that it was likely to
include individuals with a normal QT interval.13
The analysis of 1300 family members with a normal QT interval (<440 ms) of the probands of LQTS families enrolled in the International Registry supported this concept; 6% of them experienced syncope or cardiac arrest.14 This strongly suggested that they were affected by LQTS even though their QT was normal. In 1992, Vincent et al15 reported that of 82 gene carriers from 3 LQT1 families, 5 (6%) had a normal QT interval. This significant step proved that it is possible to be a gene carrier without a prolonged QT interval; conversely, because most gene carriers in these 3 families had the full phenotype, the leading laboratories continued to assume a penetrance of 90%.9 10 11 12 The present study ends the question by identifying gene carriers with a normal QT and normal phenotype in 5 different families and by demonstrating the existence of very low penetrance in LQTS.
To test our hypothesis, we had to focus our study on those families in which the existence of only 1 clinically affected individual was suggestive of a sporadic case, according to the traditional classification.1 However, when faced with families with only 1 clinically affected individual, there are 2 possibilities. One is that the individual is indeed the only affected member in his or her family and that no other gene carriers exist (de novo mutation); the other is that he or she is indeed the only clinically affected individual but that some other family members are gene carriers and as such may transmit the disease; in this case, we would be dealing with low penetrance. Molecular diagnosis allowed us to demonstrate which of the 2 possibilities was correct.
At variance with Vincent's report,15 only the proband in our families had the clinical phenotype. It follows that silent gene carriers may be expected not only within families with many clinically affected individuals but also within families thought to harbor only 1 sporadic case. This represents the final evidence that the spectrum of the disease is indeed very large and that it includes an unforeseen number of silent gene carriers.
The incidence of these sporadic cases has remained undefined over the
years. Our own previous gross estimate, based only on clinical
experience, was 
35%.2 The present quantitative
assessment, based on the families referred to our center, gives an
incidence of 39%. It thus seems reasonable to assume that
approximately one third of families in which the diagnosis of LQTS has
been made include these sporadic cases.
Implications for Molecular Screening
Molecular diagnosis is slowly entering clinical
practice.8 Its widespread use is delayed by the high cost
of the screening process, still performed only by research centers,
combined with the long time required to obtain results. Its
implementation as clinical routine with reimbursements requires clear
definition of the criteria for genetic screening.
Clinically affected individuals should be genotyped, because this may have implications for therapy and management.20 21 22 Still unclear is who else in the family should be tested, once the gene is identified in the proband. Borderline cases could also benefit, because molecular screening would provide a definitive diagnosis, thus ending their doubts. The present findings conclusively demonstrate that penetrance may be so low that in certain families, several members would escape clinical diagnosis despite being gene carriers. In our opinion, performance of molecular screening in these family members as well should no longer be optional. As proponents of a more widespread clinical use of molecular diagnosis, it seems appropriate for us to indicate the availability of our group to perform these tests free of charge in the family members of genotyped probands.
The limitations manifested here by the clinical diagnostic criteria9 16 are the direct consequence of the design of the present study, which has selected families with apparently only 1 member affected. These limitations are not encountered when we are dealing with families in which LQTS+ has a high penetrance.23 For families with few obviously affected individuals, the use of other diagnostic criteria not yet entered into widespread clinical practice may be useful.24 25 26 27 28
Our data also show that some individuals previously considered to be affected by LQTS are not gene carriers. All 3 were diagnosed as affected on the basis of their being family members of a typical LQTS patient (prolonged QT and syncope) and of being males, all with a QTc of 450 ms. This finding calls for caution before diagnosing LQTS in family members with just a modest QT prolongation.
It is conceptually and practically important to realize that the low
penetrance demonstrated here in some families affected by LQTS is not
dictated by the localization of the mutations involved. Indeed,
although a "forme fruste" of LQTS has been reported with a mutation
in the C-terminal domain of KvLQT1,29
it now appears that this phenomenon may be also associated with
mutations located in the S1-S6 regions of both KvLQT1 and
HERG. Furthermore, the mutation A561V, originally described
as being associated with high penetrance5 and
recognized later as being a mutational hot spot,19 has now
also been found to be associated with a penetrance as low as 25%
(Figures 2 and 3). This points to the fact that
penetrance does not depend solely on the specific mutations and that it
can be profoundly modified by other factors not yet identified.
Finally, the possibility that symptomatic patients carry 2
mutations ("compound heterozygotes") cannot be ruled out.
Implications for Clinical Management
The existence of LQTS families with a very low penetrance has
multiple clinical implications, all stemming from the fact that an
individual who was, and without molecular biology always would have
been, considered perfectly healthy is suddenly recognized as a gene
carrier for a potentially lethal disease. This individual has the risk
of developing a life-threatening arrhythmia and of transmitting
the disease to 50% of his or her offspring.
Among our 15 family members found to be gene carriers, only 3 were <30 years old, and all the others were >40 years old. Because LQTS usually manifests itself at a young age, this suggests that these individuals are likely to remain asymptomatic. Conversely, the alteration in repolarizing currents produced by their mutations, even without overt ECG changes, clearly predisposes to the possible occurrence of drug-induced torsade de pointes.30 31 These individuals should be informed about this possibility and be alerted to avoid all drugs, cardiac and noncardiac, that block potassium currents and also situations in which hypokalemia might occur.32 Accordingly, they should receive a comprehensive, updated list of these compounds. With rare exceptions,17 LQTS is an autosomal dominant disease, and these silent gene carriers should be informed that 50% of their offspring may be expected to carry the same mutations. Molecular diagnosis therefore has to be scheduled for their newborn infants, unless they have obvious QT prolongations.
Should any of these infants be diagnosed as a gene carrier, no assumptions on their being at low risk could be derived from the fact that the affected parent was asymptomatic. In our families, asymptomatic gene carriers were found upstream and downstream with respect to the proband. Thus, parents without the LQTS phenotype may generate highly symptomatic individuals, and symptomatic parents may generate gene carriers with a silent disease.
This report should affect the way physicians deal with LQTS families and has potential medicolegal implications. Contrary to current practice, it is no longer possible to reassure family members of LQTS probands that they are not disease carriers if they have a normal ECG. LQTS should no longer be excluded on purely clinical grounds. Such a significant statement will require the support of a molecular screening negative for the mutations present in the affected patient.
Received June 1, 1998; revision received September 30, 1998; accepted October 22, 1998.
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D. J. Tester, M. L. Will, C. M. Haglund, and M. J. Ackerman Effect of Clinical Phenotype on Yield of Long QT Syndrome Genetic Testing J. Am. Coll. Cardiol., February 21, 2006; 47(4): 764 - 768. [Abstract] [Full Text] [PDF]
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P. J. Schwartz, C. Spazzolini, L. Crotti, J. Bathen, J. P. Amlie, K. Timothy, M. Shkolnikova, C. I. Berul, M. Bitner-Glindzicz, L. Toivonen, et al. The Jervell and Lange-Nielsen Syndrome: Natural History, Molecular Basis, and Clinical Outcome Circulation, February 14, 2006; 113(6): 783 - 790. [Abstract] [Full Text] [PDF]
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C. L. Anderson, B. P. Delisle, B. D. Anson, J. A. Kilby, M. L. Will, D. J. Tester, Q. Gong, Z. Zhou, M. J. Ackerman, and C. T. January Most LQT2 Mutations Reduce Kv11.1 (hERG) Current by a Class 2 (Trafficking-Deficient) Mechanism Circulation, January 24, 2006; 113(3): 365 - 373. [Abstract] [Full Text] [PDF]
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C. R. Bezzina, W. Shimizu, P. Yang, T. T. Koopmann, M. W.T. Tanck, Y. Miyamoto, S. Kamakura, D. M. Roden, and A. A.M. Wilde Common Sodium Channel Promoter Haplotype in Asian Subjects Underlies Variability in Cardiac Conduction Circulation, January 24, 2006; 113(3): 338 - 344. [Abstract] [Full Text] [PDF]
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M. Shah, F. G. Akar, and G. F. Tomaselli Molecular Basis of Arrhythmias Circulation, October 18, 2005; 112(16): 2517 - 2529. [Abstract] [Full Text] [PDF]
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A. D. Krahn, M. Gollob, R. Yee, L. J. Gula, A. C. Skanes, B. D. Walker, and G. J. Klein Diagnosis of Unexplained Cardiac Arrest: Role of Adrenaline and Procainamide Infusion Circulation, October 11, 2005; 112(15): 2228 - 2234. [Abstract] [Full Text] [PDF]
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L. Crotti, A. L. Lundquist, R. Insolia, M. Pedrazzini, C. Ferrandi, G. M. De Ferrari, A. Vicentini, P. Yang, D. M. Roden, A. L. George Jr, et al. KCNH2-K897T Is a Genetic Modifier of Latent Congenital Long-QT Syndrome Circulation, August 30, 2005; 112(9): 1251 - 1258. [Abstract] [Full Text] [PDF]
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S. Kaab and E. Schulze-Bahr Susceptibility genes and modifiers for cardiac arrhythmias Cardiovasc Res, August 15, 2005; 67(3): 397 - 413. [Abstract] [Full Text] [PDF]
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S. Demolombe, C. Marionneau, S. Le Bouter, F. Charpentier, and D. Escande Functional genomics of cardiac ion channel genes Cardiovasc Res, August 15, 2005; 67(3): 438 - 447. [Abstract] [Full Text] [PDF]
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A. J. Wilson, K. V. Quinn, F. M. Graves, M. Bitner-Glindzicz, and A. Tinker Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1) Cardiovasc Res, August 15, 2005; 67(3): 476 - 486. [Abstract] [Full Text] [PDF]
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P. Brugada, R. Brugada, J. Brugada, S. G. Priori, C. Napolitano, P. Brugada, R. Brugada, J. Brugada, S. G. Priori, and C. Napolitano Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation, July 12, 2005; 112(2): 279 - 292. [Full Text] [PDF]
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G. Choi, L. J. Kopplin, D. J. Tester, M. L. Will, C. M. Haglund, and M. J. Ackerman Spectrum and Frequency of Cardiac Channel Defects in Swimming-Triggered Arrhythmia Syndromes Circulation, October 12, 2004; 110(15): 2119 - 2124. [Abstract] [Full Text] [PDF]
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W. Shimizu, M. Horie, S. Ohno, K. Takenaka, M. Yamaguchi, M. Shimizu, T. Washizuka, Y. Aizawa, K. Nakamura, T. Ohe, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: Multicenter study in Japan J. Am. Coll. Cardiol., July 7, 2004; 44(1): 117 - 125. [Abstract] [Full Text] [PDF]
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P. J. Schwartz Stillbirths, Sudden Infant Deaths, and Long-QT Syndrome: Puzzle or Mosaic, the Pieces of the Jigsaw Are Being Fitted Together Circulation, June 22, 2004; 109(24): 2930 - 2932. [Full Text] [PDF]
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B. J. Maron, B. R. Chaitman, M. J. Ackerman, A. Bayes de Luna, D. Corrado, J. E. Crosson, B. J. Deal, D. J. Driscoll, N.A. M. Estes III, C. G. S. Araujo, et al. Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases Circulation, June 8, 2004; 109(22): 2807 - 2816. [Abstract] [Full Text] [PDF]
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S. G. Priori Inherited Arrhythmogenic Diseases: The Complexity Beyond Monogenic Disorders Circ. Res., February 6, 2004; 94(2): 140 - 145. [Abstract] [Full Text] [PDF]
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S. G. Priori, P. J. Schwartz, C. Napolitano, R. Bloise, E. Ronchetti, M. Grillo, A. Vicentini, C. Spazzolini, J. Nastoli, G. Bottelli, et al. Risk Stratification in the Long-QT Syndrome N. Engl. J. Med., May 8, 2003; 348(19): 1866 - 1874. [Abstract] [Full Text] [PDF]
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S. M. Al-Khatib, N. M. A. LaPointe, J. M. Kramer, and R. M. Califf What Clinicians Should Know About the QT Interval JAMA, April 23, 2003; 289(16): 2120 - 2127. [Abstract] [Full Text] [PDF]
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D. M. Roden The problem, challenge and opportunity of genetic heterogeneity in monogenic diseases predisposing to sudden death J. Am. Coll. Cardiol., July 17, 2002; 40(2): 357 - 359. [Full Text] [PDF]
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G. Lande, F. Kyndt, I. Baro, D. Chabannes, P. Boisseau, J.-C. Pony, D. Escande, and H. Le Marec Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype Eur. Heart J., March 1, 2001; 22(5): 410 - 422. [Abstract] [PDF]
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C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
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S. G. Priori, C. Napolitano, N. Tiso, M. Memmi, G. Vignati, R. Bloise, V. Sorrentino, and G. A. Danieli Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia Circulation, January 16, 2001; 103(2): 196 - 200. [Abstract] [Full Text] [PDF]
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S. G. Priori, R. Bloise, and L. Crotti The long QT syndrome Europace, January 1, 2001; 3(1): 16 - 27. [PDF]
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A. A. M. Wilde and D. M. Roden Predicting the Long-QT Genotype From Clinical Data : From Sense to Science Circulation, December 5, 2000; 102(23): 2796 - 2798. [Full Text] [PDF]
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