Europace Advance Access originally published online on March 16, 2006
Europace 2006 8(4):241-244; doi:10.1093/europace/eul012
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ELECTROPHYSIOLOGY
Phenotype reveals genotype in a Greek long QT syndrome family
1 Division of Inherited Cardiovascular Diseases, 1st Department of CardiologyUniversity of Athens Medical School99 Michalakopoulou Street, Athens 11528 Greece; 2 Department of Medical GeneticsChild Health Institute, University of IstanbulIstanbul Turkey
Manuscript submitted 8 February 2005. Accepted after revision 3 January 2006.
* Corresponding author. Tel: +30 210 7231780; fax: +30 210 7256535. E-mail address: mckotta{at}hotmail.com
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Abstract |
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We aimed to verify the long QT syndrome (LQTS) genotype in a family with strong evidence of LQTS type 1 (LQT1) on the basis of so far established genotype–phenotype correlations. Genetic testing for mutations in the KCNQ1 potassium channel gene revealed an A341V mutation in three generations of the family. Existing genotype–phenotype correlations were correctly predictive of the genotype in the case of this family, despite the fact that there are no previously reported data for the Greek LQTS genetic pool. Thus, genotype–phenotype correlations are often a helpful tool in the management of LQTS patients and their families.
Key Words: Long QT syndrome, Syncope, Genotype, Phenotype
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Introduction |
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The long QT syndrome (LQTS) is an inherited cardiac ion channel disease with a characteristic prolongation of the QT interval in the electrocardiogram (ECG), which manifests as ventricular tachyarrhythmias and sudden cardiac death. Most genes that have so far been implicated in disease pathogenesis encode cardiac ion channels, with KCNQ1 (LQTS type 1, LQT1), KCNH2 (LQT2), and SCN5A (LQT3) representing the most often mutated genes responsible for LQTS. Data from the International LQTS Registry provided evidence that the particular genotype can affect the clinical course of the disease and serve as the appropriate substrate for the manifestation of cardiac events upon specific triggers.1
–3 In addition, ECG parameters that extend beyond QT interval duration have also been employed for the identification of LQTS patients4 and specific patterns of ST-T wave morphology have been assigned to the most prevalent genotypes.5 Finally, it has been demonstrated that among LQTS patients, there are gender-related differences that exert an effect on risk of a first cardiac event in an age-dependent manner.6 This report describes the phenotype-directed genetic analysis of a Greek LQTS family. |
Case report |
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A male aged 10 (Figure 1, III:6) came for treatment at the 1st Department of Cardiology, University of Athens, after experiencing a syncopal episode that was reportedly triggered during school gymnastics. The patient underwent complete clinical evaluation, including 12-lead ECG, echocardiography, and 24-h Holter monitoring. ECG showed a prolonged QT interval and QTc was 475 ms. The patient had a history of recurrent syncopal episodes ever since 8 years of age, all reportedly triggered by exercise, as well as a family history of sudden death that occurred after swimming. A score of 4.5 points suggested a high probability for LQTS according to the previously proposed diagnostic criteria.7
Clinical examination of all family members revealed that in total, five had a definite clinical diagnosis of LQTS (Table 1). The ST-T wave patterns of several family members' ECGs were normal-appearing at the time of initial evaluation.
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Recurrent syncopal episodes of early onset (
15 years) that were triggered by exercise, as well as normal-appearing, long T-wave duration patterns were suggestive of an LQT1 genotype. All family members or their guardians gave written informed consent for genetic testing. Mutation detection involved PCR–SSCP analysis followed by automated sequencing. The oligonucleotide primers used have been previously reported8 and some were redesigned. The investigation conformed to the principles outlined in the Declaration of Helsinki (Cardiovascular Research 1997;35:2–4) and was approved by the Institution's Ethics Committee.
Genetic testing for mutations in the KCNQ1 gene verified the suspicion of an LQT1 genotype. The index patient carried the previously described A341V mutation9–13 (Figure 2). Genetic analysis expanded to the rest of the family revealed that all affected were mutation carriers, plus a child with borderline clinical diagnosis (III:1), and another who was asymptomatic with normal ECG despite consecutive evaluations (III:5). Average penetrance in the family was found to be 71% and was rather high.14 In this context, all affected were treated with ß-blockers. The family has been followed-up for a 3-year period during which all patients that had previously experienced syncope remain completely asymptomatic.
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Discussion |
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We have previously reported that in the region of Attica and the Cyclades islands, in 130 consecutive cases of sudden death recorded over a 4-year period, 74% were attributed to cardiovascular causes after post-mortem examination, whereas 22% remained of unknown cause.15
Although these cases of unknown cause of sudden death have not been explored by genetic analysis, it is estimated that non-structural heart disease, such as the LQTS, the Brugada syndrome, or exercise-induced polymorphic ventricular tachycardia, could be the cause of sudden death in a number of these cases.16
We hereby report the phenotype-directed genetic diagnosis of a Greek LQTS family. The family carries an A341V mutation in the KCNQ1 gene that is a loss-of-function type mutation.17 Alanine in codon 341 has been designated as a mutational hot spot, reportedly often mutated even in different populations.17,12 Although the family had a history of sudden death, the overall picture is that of recurrent syncopal episodes initiated before 15 years of age for both male and female members. The latter had also suffered cardiac events during adulthood and presented slightly longer QTc on ECG (Table 1). It has been previously reported that by age 15, there is a higher risk of a first cardiac event in LQT1 males than females; however, the total number of events is significantly higher in LQT1 females.18 In this study, affected male children had reportedly experienced more events by 15 years than females by the same age, but as all children are still underage, no comparison can be made on the incidence of events between childhood and adulthood. The common factor, however, is an early onset of cardiac events that have been triggered by exercise, which in addition to normal-appearing T wave patterns in the ECG, constitutes a typical clinical picture of LQT1.
On the basis of clinical criteria such as family history, ECG patterns, symptoms, specific triggers, and age of onset, genetic analysis of the family was correctly directed towards an LQT1 genotype. In a previous study by Van Langen et al.19 involving 40 LQTS patients, a phenotype-directed genotyping strategy was adopted. The attempt to predict the genotype by integrating phenotypic information, such as age of onset, specific triggers, and family history with ECG data was successful in 90% of all genotyped cases. In addition, when the most probable gene was screened in a putative LQT subgroup, a mutation was found in 70% of all cases. This screening strategy is very time and cost effective and allows a relatively fast genetic diagnosis that would be otherwise hampered by issues of genetic heterogeneity. However, it must be noted that selective phenotypic information, such as ECG data, can sometimes be misleading if a genotyping strategy is to be adopted.20
Although factors such as age, gender, specific triggers, and ECG characteristics have altogether an ‘added value’ in genotype prediction19 and are integrated features of the clinical outcome of a given genetic substrate, their interpretation in an attempt to link phenotype with genotype may be endangered by our lack of knowledge of other modifying factors that lie in between. In populations such as ours, where there is yet no information on the prevalence of the genes involved, existing genotype–phenotype correlations could be a starting point for a systematic exploration and registration of the Greek LQTS genetic pool, which would in turn contribute to a more effective management of patients and their families.
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Acknowledgements |
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This work was supported by the Research Grants Account of the University of Athens and the General Secretariat of Research and Technology, Ministry of Development.
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References |
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