Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes.
ABSTRACT Congenital long-QT syndrome (LQTS) is caused by mutations of genes encoding the slow component of the delayed rectifier current (LQT1, LQT5), the rapid component of the delayed rectifier current (LQT2, LQT6), or the Na(+) current (LQT3), resulting in ST-T-wave abnormalities on the ECG. This study evaluated the spectrum of ST-T-wave patterns and repolarization parameters by genotype and determined whether genotype could be identified by ECG.
ECGs of 284 gene carriers were studied to determine ST-T-wave patterns, and repolarization parameters were quantified. Genotypes were identified by individual ECG versus family-grouped ECG analysis in separate studies using ECGs of 146 gene carriers from 29 families and 233 members of 127 families undergoing molecular genotyping, respectively. Ten typical ST-T patterns (4 LQT1, 4 LQT2, and 2 LQT3) were present in 88% of LQT1 and LQT2 carriers and in 65% of LQT3 carriers. Repolarization parameters also differed by genotype. A combination of quantified repolarization parameters identified genotype with sensitivity/specificity of 85%/70% for LQT1, 83%/94% for LQT2, and 47%/63% for LQT3. Typical patterns in family-grouped ECGs best identified the genotype, being correct in 56 of 56 (21 LQT1, 33 LQT2, and 2 LQT3) families with mutation results.
Typical ST-T-wave patterns are present in the majority of genotyped LQTS patients and can be used to identify LQT1, LQT2, and possibly LQT3 genotypes. Family-grouped ECG analysis improves genotype identification accuracy. This approach can simplify genetic screening by targeting the gene for initial study. The multiple ST-T patterns in each genotype raise questions regarding the pathophysiology and regulation of repolarization in LQTS.
SourceAvailable from: Guoliang Li[Show abstract] [Hide abstract]
ABSTRACT: Mutations in the human ether‐a‐go‐go‐related gene (hERG) are responsible for congenital Type 2 long QT syndrome (LQT2). Previously, we reported a truncated mutation of hERG in a Chinese family with LQT2, namely L539 fs/47, which is composed of a 19 bp deletion mutation and an A1692G polymorphism. This mutation was found to cause an LQT2 phenotype. The aim of the present study was to investigate the functional role of L539 fs/47 at the cellular level and its potential contribution to the loss of function of hERG channels.The function of the truncated mutation L539 fs/47 was evaluated by constructing a mutated plasmid, transfection of the mutated cDNA into HEK 293 cells and subsequent patch‐clamp, western blotting and immunostaining experiments.Homologous expression of L539 fs/47 in HEK 293 cells produced a non‐functional protein that was detected in cell membranes. When L539 fs/47 was expressed simultaneously with wild‐type hERG, it suppressed wild‐type hERG currents in a dose‐dependent manner and changed the gating properties of the channel.Although L539 fs/47 hERG proteins were detected on plasma membranes, they failed to generate hERG currents. In general, L539 fs/47 dose‐dependently decreases hERG ion channel currents and suppresses the function of wild‐type channels function. This may explain, in part, the clinical manifestations of LQT2 in the family with this mutation.Clinical and Experimental Pharmacology and Physiology 01/2013; 40(1). DOI:10.1111/1440-1681.12028 · 2.41 Impact Factor
Article: [Ion channel diseases in children.][Show abstract] [Hide abstract]
ABSTRACT: Ion channel diseases are responsible for the occurrence of supraventricular bradycardia and tachycardia, ventricular tachycardia, syncope and sudden death. In the present paper the specific considerations for diagnostic pathways and therapeutic decision making will be focused on for the largest clinical entities, such as the long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia and Andersen-Tawil syndrome. All diseases are characterized by a specific pathognomic electrocardiographic (ECG) alteration. For most of the diseases a variety of mutations have been identified that code for different ion channel proteins. All have a high potential of arrhythmogenicity in common. It is important to know that the ECG alterations are often only transient, which makes repetitive recordings and sometimes provocation maneuvers necessary. The time of onset of disease varies so that the initiation of diagnostics starts at different ages. Therapy often remains an individual choice and is influenced by a number of factors, such as a family history of sudden death.Herzschrittmachertherapie & Elektrophysiologie 08/2014; DOI:10.1007/s00399-014-0325-7