A gain of function mutation N588K in the KCNH2 gene that encodes HERG channels 
has been shown to underlie the SQT1 form of short QT syndrome (SQTS). We 
describe a different mutation in the KCNH2 gene in a Chinese family with 
clinical evidence of SQTS. A Chinese family with a markedly short QT interval 
(QTc=316 ± 9 ms, n=4) and a strong family history of sudden death was 
investigated. Analysis of candidate genes contributing to ventricular 
repolarization identified a C1853T mutation in the KCNH2 gene coding for the 
HERG channel, resulting in an amino acid change (T618I) that was found to 100% 
co-segregate with the SQTS phenotype (n=4). Whole cell voltage clamp studies of 
the T618I mutation in HEK-cells demonstrated a 6-fold increase in maximum steady 
state current (146.1 ± 16.7 vs 23.8 ± 5.5 pA/pF) that occurred at a 20 mV more 
positive potential compared to the wild type channels. The voltage dependence of 
inactivation was significantly shifted in the positive voltage direction (WT 
-78.6 ± 6.8 vs T618I -29.3 ± 1.7 mV). Kinetic analysis revealed slower 
inactivation rates of T618I but faster rates of recovery from inactivation. 
Quinidine (5 μM) and sotalol (500 μM) had similar inhibitory effects on steady 
currents measured at +20 mV in WT and T618I but were less effective in 
inhibiting tail currents of mutant channels. The altered function of T618I-HERG 
channels suggests that this mutation in the KCNH2 gene is responsible for the 
SQTS phenotype in this family. Both quinidine and sotalol may be therapeutic 
options for patients with the T618I HERG mutation.