25th Anniversary of the International Long-QT Syndrome Registry: An Ongoing Quest to Uncover the Secrets of Long-QT Syndrome

Cardiology Unit of the Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Circulation (Impact Factor: 14.43). 04/2005; 111(9):1199-201. DOI: 10.1161/01.CIR.0000157069.91834.DA
Source: PubMed


oday, it is exceptional to find a major cardiology con- gress without a session devoted to the long-QT syndrome (LQTS), but it was quite different 25 years ago when the minuscule knowledge about LQTS was paralleled only by the minute number of investigators interested in what seemed to be little more than a medical oddity. Partly by chance, the two of us had actually and independently developed a rather burning interest and curiosity for this often lethal hereditary disorder that is spiced by several unique features. 1-4 We joined forces with the goal of unraveling this mysterious disease by establishing a prospective International Registry for LQTS. The main objectives were those to gain insight into the natural history, clinical course, and efficacy of current and novel therapies. When molecular biology techniques matured to the point of making possible the identification of disease- causing genes and disease-causing mutations, what became essential was the availability of numerous and well- developed clinical pedigrees providing clear separation be- tween "affected" and "nonaffected" individuals. This is what the Registry was able to provide and where it played a decisive role in sharing with molecular biologists the ideal material for their analysis. In 1979, when the Registry was established, it did not escape us that this long-term project was likely to contribute to a better understanding and management of LQTS. Quite frankly, however, we did not anticipate the explosion of knowledge that would result from the genetic and molecular findings of the 1990s and the central role that the Registry, with its well-defined clinical phenotypes and family pedi- grees, would play in uncovering the secrets of this disorder. Additionally, we could not have fathomed the now clear evidence that LQTS indeed represents a paradigm for the understanding of sudden cardiac death in more common cardiac diseases. Objectives Our primary objective with the International LQTS Registry was to gain insight into the natural history and clinical course of this hereditary repolarization disorder so that more effec- tive therapy could be rendered to prevent the syncope and sudden death events that frequently accompanied LQTS. Impact The International LQTS Registry has enhanced our knowl- edge base of an infrequently occurring cardiac disorder, and it has become a paradigm for studying such conditions. The diagnostic criteria for LQTS have been established.5 The cardiologists associated with the Registry continue to offer physicians from around the world an opportunity to obtain advice on how to manage their LQTS patients. This exchange between the Registry cardiologists and physicians became a mutually beneficial interaction because these physicians also contributed clinical data to the Registry by willingly com- pleting enrollment and yearly follow-up data forms. This approach allowed us to gather information on an impressive number of patients and, of crucial importance for the subse- quent genetic developments, on first- and second-degree family relatives. Over the years, the growing knowledge in LQTS was shared with the profession through scientific publications, chapters in cardiology textbooks, personal com- munications, and recently, an Internet-based virtual LQTS symposium ( Subsequently, similar types of registries were established by interested investigators for other uncommon cardiac dis- orders, including hypertrophic cardiomyopathy, arrhythmo- genic right ventricular cardiomyopathy, and Brugada syn- drome. It is gratifying to know that the International LQTS Registry helped to pave the way for scientific progress in the difficult field of uncommon diseases.

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    • "The International Long QT Syndrome Registry was founded in 1979, and various clinical and genetic studies, including many prospective studies, have been extracted from this registry (9, 10). In Korea, however, there have been only a few studies for LQTS regarding clinical and ECG findings (11) or genomic sequences (12) only in small study populations. "
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    ABSTRACT: The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc ≥ 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.
    Journal of Korean medical science 10/2013; 28(10):1454-60. DOI:10.3346/jkms.2013.28.10.1454 · 1.27 Impact Factor
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    • "Disease registries, especially for rare diseases, are becoming valuable resources for obtaining and reporting information [Basso et al., 2004; Moss and Schwartz, 2005; Wilkinson et al., 2010; Byrne et al., 2011; Clarke et al., 2011]. Centralized longitudinal and natural history data as well as the potential to link specific clinical data with DNA or tissue specimens are becoming useful tools for evaluating pathophysiology, genotype–phenotype correlation, genetic modifiers , and potential therapies [Basso et al., 2004; Moss and Schwartz, 2005; Wilkinson et al., 2010]. Registries are also recognized for the potential to evaluate outcomes and efficacies of certain therapies [Basso et al., 2004; Clarke et al., 2011] and are increasingly being used by industry for this purpose in rare diseases [Byrne et al., 2011; Clarke et al., 2011]. "
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    ABSTRACT: Barth syndrome (BTHS); MIM accession # 302060) is a rare X-linked recessive cardioskeletal mitochondrial myopathy with features of cardiomyopathy, neutropenia, and growth abnormalities. The objectives of this study were to further elucidate the natural history, clinical disease presentation, and course, and describe growth characteristics for males with BTHS. Patients with a confirmed genetic diagnosis of BTHS are referred to the BTHS Registry through the Barth Syndrome Foundation, self-referral, or physician referral. This study is based on data obtained from 73 subjects alive at the time of enrollment that provided self-reported and/or medical record abstracted data. The mean age at diagnosis of BTHS was 4.04 ± 5.45 years. While the vast majority of subjects reported a history of cardiac dysfunction, nearly 6% denied any history of cardiomyopathy. Although most subjects had only mildly abnormal cardiac function by echocardiography reports, 70% were recognized as having cardiomyopathy in the first year of life and 12% have required cardiac transplantation. Of the 73 enrolled subjects, there have been five deaths. Growth curves were generated demonstrating a shift down for weight, length, and height versus the normative population with late catch up in height for a significant percentage of cases. This data also confirms a significant number of patients with low birth weight, complications in the newborn period, failure to thrive, neutropenia, developmental delay of motor milestones, and mild learning difficulties. However, it is apparent that the disease manifestations are variable, both over time for an individual patient and across the BTHS population. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 11/2012; 158A(11):2726-32. DOI:10.1002/ajmg.a.35609 · 2.16 Impact Factor
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    • "Management of LQTS involves ongoing collaboration between cardiologist, clinical geneticist, molecular pathologist and cardiac electrophysiologist, to ensure that the strengths and weaknesses of genetic testing in this condition are understood. The international Long QT syndrome registry has considerably enhanced knowledge of the genetics of LQTS [82] but we are still far from full understanding of this complex condition. "
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    ABSTRACT: Long QT syndrome (LQTS) is a cardiac disorder associated with sudden death especially in young, seemingly healthy individuals. It is characterised by abnormalities of the heart beat detected as lengthening of the QT interval during cardiac repolarisation. The incidence of LQTS is given as 1 in 2000 but this may be an underestimation as many cases go undiagnosed, due to the rarity of the condition and the wide spectrum of symptoms. Presently 12 genes associated with LQTS have been identified with differing signs and symptoms, depending on the locus involved. The majority of cases have mutations in the KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) genes. Genetic testing is increasingly used when a clearly affected proband has been identified, to determine the nature of the mutation in that family. Unfortunately tests on probands may be uninformative, especially if the defect does not lie in the set of genes which are routinely tested. Novel mutations in these known LQTS genes and additional candidate genes are still being discovered. The functional implications of these novel mutations need to be assessed before they can be accepted as being responsible for LQTS. Known epigenetic modification affecting KCNQ1 gene expression may also be involved in phenotypic variability of LQTS. Genetic diagnosis of LQTS is thus challenging. However, where a disease associated mutation is identified, molecular diagnosis can be important in guiding therapy, in family testing and in determining the cause of sudden cardiac death. New developments in technology and understanding offer increasing hope to families with this condition.
    Molecular Genetics and Metabolism 09/2010; 101(1):1-8. DOI:10.1016/j.ymgme.2010.05.011 · 2.63 Impact Factor
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