Harrell Daniel Toshio, Ashihara Takashi, Ishikawa Taisuke, Tominaga Ichiko, Mazzanti Andrea, Takahashi Kazuhiro, Oginosawa Yasushi, Abe Haruhiko, Maemura Koji, Sumitomo Naokata, Uno Kikuya, Takano Makoto, Priori Silvia G, Makita Naomasa
Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Heart Rhythm Center, Shiga, Japan.
Int J Cardiol. 2015;190:393-402. doi: 10.1016/j.ijcard.2015.04.090. Epub 2015 Apr 15.
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.
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.
We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.
短QT综合征（SQTS）是一种罕见的遗传性心律失常，与心房和心室颤动相关，由六个具有高外显率的心脏离子通道基因突变引起。然而，SQTS患者之间基因型特异性的临床差异仍有待阐明。
我们筛查了五个不相关的日本SQTS家系，在KCNH2和KCNQ1中鉴定出三个突变。一个新的突变KCNH2-I560T，当在COS-7细胞中表达时，与野生型相比，峰值电流密度增加了2.5倍，失活曲线正向移位（+14 mV）。计算机模拟重现了动作电位缩短，并为心室颤动创造了致心律失常底物。在另一个携带KCNQ1-V141M突变的家系中，受影响成员表现出更早的发病年龄和频繁的缓慢性心律失常并发症。为了确定SQT1（KCNH2）、SQT2（KCNQ1）和其他亚型SQT3-6的基因型特异性表型，我们分析了先前报道的132例SQTS病例中65例突变阳性患者的临床变量。SQT1的发病年龄明显更晚（SQT1：35±19岁，n = 30；SQT2：17±25岁，n = 8；SQT3-6：19±15岁，n = 15；p = 0.011）。SQT2表现出更高的缓慢性心律失常患病率（SQT2：6/8，75%；非SQT2：5/57，9%；p < 0.001）和心房颤动患病率（SQT2：5/8，63%；非SQT2：12/57，21%；p = 0.012）。在来自16个SQTS家系的51例突变阳性个体中，9例未表现出短QT，但表现出其他心电图异常，如心房颤动。由此得出的外显率为82%，低于先前的认识。
我们提出，SQTS患者可能因其基因型不同而表现出不同的临床表现。
