BACKGROUND: Classic symptoms of long QT syndrome (LQTS) include prolongation of QT interval on electrocardiograph, syncope, and cardiac arrest due to a distinctive form of polymorphic ventricular tachycardia, known as Torsade de Pointes. We assessed occurrence of LQTS signs in individuals from 30 Czech families with mutations in KCNQ1 and KCNH2 genes. METHODS AND RESULTS: One hundred five individuals from 30 Czech families with LQTS were genotyped for KCNQ1 and KCNH2. The occurrence of typical LQTS signs (pathologic prolongation of QT interval; syncope; cardiac arrest; Torsade de Pointes) was clinically assessed by exercise test with QT interval analysis. Family history of sudden cardiac death was taken. Statistical analysis was performed to determine correlation of clinical results and mutation status. KCNQ1 gene mutations were found in 23 families, and KCNH2 gene mutations in eight families. Only 46 (70%) of the 66 mutation carriers had at least two of the typical LQTS signs. The others were minimally or asymptomatic. From 39 noncarrier individuals, only 1 fulfilled the clinical criteria of LQTS diagnosis, another 4 had an intermediate probability of diagnosis. The exercise test had 92% sensitivity and 93% specificity for LQTS diagnosis. CONCLUSIONS: Incidence of classical signs of LQTS was not high in Czech carriers of KCNQ1 and KCNH2 mutations. Therefore, proper diagnosis relies on detection of symptoms at presentation. The exercise test may be beneficial owing to its high sensitivity and specificity for LQTS diagnosis.
- MeSH
- dospělí MeSH
- draslíkové kanály ether-a-go-go genetika MeSH
- elektrokardiografie statistika a číselné údaje MeSH
- genetická predispozice k nemoci epidemiologie genetika MeSH
- hodnocení rizik MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- prevalence MeSH
- reprodukovatelnost výsledků MeSH
- RNA dlouhá nekódující genetika MeSH
- senzitivita a specificita MeSH
- syndrom dlouhého QT diagnóza epidemiologie genetika MeSH
- zátěžový test statistika a číselné údaje MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Observations from population-based studies demonstrated a strong genetic component of sudden cardiac death. The aim of this study was to test the hypothesis that ion channel genes mutations are more common in ventricular fibrillation (VF) survivors with coronary artery disease (CAD) compared to controls. METHODS: The entire coding sequence of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes was analyzed in 45 (five females) CAD individuals-survivors of documented VF and in 90 matched healthy controls. In another control group of 141 matched patients with CAD without malignant arrhythmias, the exons containing rare coding variants found in the VF survivors were sequenced. RESULTS: The carrier frequency of all the rare sequence variants was significantly higher in the VF survivors (8/45, 17.8%) than in CAD controls (3/141, 2.2%, P = 0.001). In VF survivors, four coding variants in eight individuals were found. Three in KCNH2 gene: R148W and GAG186del are novel; P347S was previously related to long QT syndrome. In SCN5A gene, P2006A variant was found in five unrelated males. This variant has been demonstrated previously to have small effect on sodium channel kinetics. No rare coding variants were found in the healthy controls. The P2006A variant was found in three CAD controls. CONCLUSION: The prevalence of selected, rare coding variants in five long QT genes was significantly higher in cases versus controls, confirming a mechanistic role for these genes among a subgroup of patients with coronary disease and VF.
- MeSH
- analýza přežití MeSH
- draslíkové kanály genetika MeSH
- fibrilace komor genetika mortalita MeSH
- genetická predispozice k nemoci epidemiologie genetika MeSH
- hodnocení rizik MeSH
- incidence MeSH
- jednonukleotidový polymorfismus genetika MeSH
- komorbidita MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- mutační analýza DNA MeSH
- nemoci koronárních tepen genetika mortalita MeSH
- přežívající MeSH
- rizikové faktory MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
The long QT syndrome (LQTS) is a monogenic disorder characterized by prolongation of the QT interval on electrocardiogram and syncope or sudden death caused by polymorphic ventricular tachycardia (torsades de pointes). In general, mutations in cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2) have been identified as a cause for LQTS. About 50-60 % of LQTS patients have an identifiable LQTS causing mutation in one of mentioned genes. In a group of 12 LQTS patients with no identified mutations in these genes we have tested a hypothesis that other candidate genes could be involved in LQTS pathophysiology. SCN1B and KCND3 genes encode ion channel proteins, ANK2 gene encodes cytoskeletal protein interacting with ion channels. To screen coding regions of genes SCN1B, KCND3, and 10 exons of ANK2 following methods were used: PCR, SSCP, and DNA sequencing. Five polymorphisms were found in screened candidate genes, 2 polymorphisms in KCND3 and 3 in SCN1B. None of found polymorphisms has coding effect nor is located close to splice sites or has any similarity to known splicing enhancer motifs. Polymorphism G246T in SCN1B is a novel one. No mutation directly causing LQTS was found. Molecular mechanism of LQTS genesis in these patients remains unclear.
- Klíčová slova
- ANK2, Candidate genes, KCND3, Long QT syndrome, SCN1B,
- MeSH
- ankyriny metabolismus MeSH
- dospělí MeSH
- draslíkové kanály Shal genetika MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- sodíkové kanály genetika MeSH
- syndrom dlouhého QT diagnóza genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il., tab. ; 30 cm
Syndrom dlouhého QT intervalu je geneticky podmíněné onemocnění spojené s vysokým výskytem maligních komorových arytmií a náhlé smrti. V polovině případů je příčinou mutace genů pro podjednotky 3 iontových kanálů myokardu. Podkladem tohoto onomocnění o dalších pacientů mohou být poškození dalších iontových kanálů, které hrají významnou roli v akčním potenciálu kadiomyocytů. Syndrom dlouhého QT intervalu vytváří model arytmogeneze na molekulární úrovni.; The Long QT syndrome is a genetically determined disease associated with high risk of malignant ventricular arrhytmias and sudden death. Half of the cases is caused by mutation of genes for 3 myocardial ion channels. Alteration of other ion channel, which play important role in action potential of cardiomyocytes, could form the disease background in the other patients. The long QT syndrome forms a molecular level of arrhytmogenesis.
- MeSH
- iontové kanály genetika MeSH
- mutace MeSH
- náhlá srdeční smrt MeSH
- srdeční arytmie MeSH
- syndrom dlouhého QT MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- kardiologie
- biologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
In a 7-year-old boy with normal hearing suffering from repeated syncope an extremely prolonged QTc interval (up to 700 ms) was found. The mother was completely asymptomatic and the father had an intermittently borderline QTc interval (maximum 470 ms) but no symptoms. In the proband a mutation analysis of KCNQ1 gene revealed a homozygous 1893insC mutation. The parents were heterozygous for this mutation. There was no consanguineous marriage in the family. The clinical relevance of these findings is that apparently normal individuals may have a latent reduction of repolarizing currents, a "reduced repolarization reserve," because they are carriers of latent ion channel genes mutations.
- MeSH
- dítě MeSH
- draslíkový kanál KCNQ1 * genetika MeSH
- elektrokardiografie metody MeSH
- genetická predispozice k nemoci genetika MeSH
- geny recesivní * genetika MeSH
- heterozygot MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mutace MeSH
- Romanův-Wardův syndrom * diagnóza genetika MeSH
- sekvence nukleotidů MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
