Long QT Syndrome: Clinical and Genetic Diagnostic Complications
Long QT Syndrome (LQTS) is associated with potentially fatal ventricular tachyarrhythmias. While modern LQTS management is quite effective, the diagnosis of this pathology today still poses a serious problem due to the fact that there is no standardized method for estimating the QT interval (different methods are used for assessment of QT interval), variability of phenotypic manifestations (asymptomatic and latent forms) and difficulties in interpreting genetic results. Currently, international experts recommend measuring the QT interval manually using the tangent or threshold method. Modern technologies of genomic sequencing and related new scientific discoveries lead to the fact that clinical evaluation algorithms and criteria of pathogenicity of genetic variants are the subject for a continuous process of reanalysis and reclassification. Thus, the growing number (now there are more than 15) of genes, the mutations of which are associated with many LQTS types can disorient clinical specialists and raise doubts among molecular geneticists regarding the pathogenicity of many registered genetic variants. Multicenter studies of recent years have shown important genotype-phenotypic correlations that are currently in demand in clinical practice for determining the treatment tactics for patients with the most common three genotypes that comprise about 85-95% of all gene-positive LQTS: KCNQ1 (LQT 1), KCNH2 (LQT 2) and SCN5A (LQT 3).In the presented article, the analysis of the recommended methods for measuring the QT interval, the overview of new system of LQTS genetic classification and LQTS risk stratification were carried out. To highlight the important concept of deep phenotyping, including cascading screening of family members with interpretation of the results of the genetic test (segregation analysis), the clinical case reports of family LQTS with the genotypes KCNQ1 (LQT 1) and SCN5A (LQT 3) were presented. This concept is of great importance for establishing an accurate LQTS diagnosis in order to avoid possible diagnostic errors, which ultimately determines the treatment strategy and prognosis of patients, the optimal choice of non-invasive or invasive methods of therapy.