@phdthesis{oai:nagasaki-u.repo.nii.ac.jp:00002970,
 author = {Harrell, Daniel Toshio},
 month = {Mar},
 note = {Background: Short QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype-specific clinical differences between SQTS patients remain to be elucidated. Methods and results: We screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift (+ 14 mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3?6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35 ± 19 years, n = 30; SQT2: 17 ± 25 years, n = 8, SQT3?6: 19 ± 15 years, n = 15; p = 0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p < 0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p = 0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized. Conclusion: We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype., 長崎大学学位論文 学位記番号:博(医歯薬)甲第1009号 学位授与年月日:平成30年3月31日, Author: Daniel Toshio Harrell, Takashi Ashihara, Taisuke Ishikawa, Ichiko Tominaga, Andrea Mazzanti, Kazuhiro Takahashi, Yasushi Oginosawa, Haruhiko Abe, Koji Maemura, Naokata Sumitomo, Kikuya Uno, Makoto Takano, Silvia G. Priori, Naomasa Makita, Citation: International Journal of Cardiology, 190, pp.393?402; 2015, Nagasaki University (長崎大学), 博士(医学) (2018-03-31)},
 school = {Nagasaki University (長崎大学)},
 title = {Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome},
 year = {2018}
}