Genetics of Long QT Syndrome

Abstract

Long QT syndrome (LQTS) is a potentially life-threatening cardiac arrhythmia characterized by delayed myocardial repolarization that produces QT prolongation and increased risk for torsades des pointes (TdP)-triggered syncope, seizures, and sudden cardiac death (SCD) in an otherwise healthy young individual with a structurally normal heart. Currently, there are three major LQTS genes (KCNQ1, KCNH2, and SCN5A) that account for approximately 75% of the disorder. For the major LQTS genotypes, genotype-phenotype correlations have yielded gene-specific arrhythmogenic triggers, electrocardiogram (ECG) patterns, response to therapies, and intragenic and increasingly mutation-specific risk stratification. The 10 minor LQTS-susceptibility genes collectively account for less than 5% of LQTS cases. In addition, three atypical LQTS or multisystem syndromic disorders that have been associated with QT prolongation have been described, including ankyrin-B syndrome, Anderson-Tawil syndrome (ATS), and Timothy syndrome (TS). Genetic testing for LQTS is recommended in patients with either a strong clinical index of suspicion or persistent QT prolongation despite their asymptomatic state. However, genetic test results must be interpreted carefully.

QTc prolongation in patients with hearing loss: Electrocardiographic and genetic study

“…However, it should be emphasized that in our study, even in patients with abnormal QTc, the mean QTc interval was only slightly prolonged -still less than 490 ms. Also, no arrhythmia or syncope were observed in any of studied patients and only 3 asymptomatic individuals had pathogenic mutations. Furthermore, despite including 3 so-called large LQTS genes (KCNQ1, KCNH2, SCN5A) responsible for approximately 75% of all LQTS cases and the KCNE1 gene (a so-called small LQTS gene) [19], we identified only 3 mutations in 6 patients that are known to be responsible for the occurrence of LQTS. Additionally, only 3 (5%) patients with mutations had a significant increase in QTc on ECG screening.…”

The heart in sickle cell disease, a model for heart failure with preserved ejection fraction

“…Such islands of impaired electrical conductivity create potential substrates for unstable ventricular tachycardias (Torsades de Pointes). Transcriptome analysis demonstrated decreased expression of SCN4B, AKAP9, CACNA1S, KCNJ2, and SCN4A, which have all been linked to long QT syndromes (18).…”

Mutation Analysis of KCNQ1, KCNH2 and SCN5A Genes in Taiwanese Long QT Syndrome Patients

“…3) Three are major LQTS genes (KCNQ1, KCNH2 and SCN5A) and 10 are minor LQTS-susceptibility genes (AKAP9, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNJ5, SC-N4B, and SNTA1). 4) Approximately 75% of patients with a clinically robust LQTS have mutations in one of the 3 major LQTS-causing genes (KCNQ1, 35%; KCNH2, 30%; and SC-N5A, 10%). Less than 5% of LQTS cases have mutations in the 10 minor LQTS-susceptibility genes.…”

“…It is a closed-tube method, meaning that PCR amplification and subsequent analysis are sequentially performed in the well. Therefore, HRM analysis can be applied for high throughput muta-Vol 56 No 4 GENETICS OF LONG QT SYNDROME IN TAIWAN tion scanning of genes for which large samples must be investigated.…”