Abstract
SummaryFor long QT syndrome (LQTS), recent progress in genome-sequencing technologies enabled the identification of rare genomic variants with diagnostic, prognostic, and therapeutic implications. However, pathogenic stratification of the identified variants remains challenging, especially in variants of uncertain significance. This study aimed to propose a phenotypic cell-based diagnostic assay for identifying LQTS to recognize pathogenic variants in a high-throughput manner suitable for screening. We investigated the response of LQT2-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) following IKr blockade using a multi-electrode array, finding that the response to IKr blockade was significantly smaller than in Control-iPSC-CMs. Furthermore, we found that LQT1-iPSC-CMs and LQT3-iPSC-CMs could be distinguished from Control-iPSC-CMs by IKs blockade and INa blockade, respectively. This strategy might be helpful in compensating for the shortcomings of genetic testing of LQTS patients.
Highlights
Long QT syndrome (LQTS) is caused by hereditary cardiac channelopathies characterized by a prolonged QT interval and abnormal T-wave morphology on electrocardiograms and capable of precipitating malignant arrhythmia (i.e., Torsade de Pointes [TdP]), resulting in syncope and sudden death (Moss, 2003)
Clinical Phenotype of LQTS Patients Enrolled in this Study and Genetic Mutations All patients enrolled in this study were symptomatic, except for an LQT2 patient harboring potassium voltage-gated channel subfamily H member 2 (KCNH2) p.G601S (Table 1)
We evaluated action potential duration (APD) to assess the contribution of IKr to repolarization (Figure 3C), finding that the APD90 in Control, LQT2A422T, and LQT2 A422T-corr-induced pluripotent stem cell (iPSC)-CMs was 215.8 ± 16.2 ms, 321.1 ± 37.0 ms, and 216.4 ± 24.4 ms, respectively (p < 0.05), whereas the AP amplitude and maximum diastolic potential (MDP) did not differ significantly (Figure 3D)
Summary
Long QT syndrome (LQTS) is caused by hereditary cardiac channelopathies characterized by a prolonged QT interval and abnormal T-wave morphology on electrocardiograms and capable of precipitating malignant arrhythmia (i.e., Torsade de Pointes [TdP]), resulting in syncope and sudden death (Moss, 2003). Genetic tests are currently utilized to assist treatment selection and prognostication (Napolitano et al, 2005); the advent of high-output sequencing techniques using next-generation sequencing has allowed identification of an extremely large number of variants from both patients and healthy individuals. Given the extreme clinical importance of identifying pathogenic variants among those of uncertain significance (i.e., VUSs) (Horie, 2016), a phenotype-based high-throughput diagnostic test is required to identify clinically relevant genetic abnormalities. Giudicessi and Ackerman (2013) suggested ‘‘currentcentric’’ classification of LQTS-susceptibility genes, which is reasonable in terms of phenotype-based diagnosis and subsequent treatment selection. Current-centric classification is difficult in clinical settings. The use of provocative tests, including exercise-stress tests and druginfusion tests, has been proposed to predict the LQTS genotypes, it remains difficult to appropriately diagnose and manage decisions based on their results (Priori et al, 2013)
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