Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome.

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.

• Authors: 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
• Journal: International journal of cardiology (Int J Cardiol) Vol. 190 Pg. 393-402 ( 2015) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 25974115 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Topics

• Adolescent
• Adult
• Age of Onset
• Aged
• Arrhythmias, Cardiac (complications, diagnosis, genetics)
• Child
• Child, Preschool
• Cohort Studies
• Female
• Genotype
• Humans
• Male
• Middle Aged
• Mutation (genetics)
• Pedigree
• Young Adult