Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome. (1st July 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: International journal of cardiology. Volume 190(2015)
• Page Start: 393
• Page End: 402
• Publication Date: 2015-07-01
• Subjects: Short QT syndrome -- Mutation -- Patch clamp -- Meta-analysis -- Computer simulation; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2015.04.090
• Languages: English
• ISSNs: 0167-5273

Abstract

Abstract: 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. Highlights: We found 3 mutations including a novel KCNH2 -I560T in 5 Japanese SQTS families. We clinically evaluated 65 previously known mutation-positive SQTS patients. SQT1 patients showed later onset of age of manifestation than non-SQT1 subgroup. Bradycardia and AF were more prevalent in SQT2 patients than in non-SQT2 subgroup. Clinical characteristics of SQTS can differ depending on genotype.