title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Daniel Toshio
authors.initials: DT
authors.lastname: Harrell
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Heart Rhythm Center, Shiga, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashihara
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Ichiko
authors.initials: I
authors.lastname: Tominaga
authors.affiliation: Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mazzanti
authors.affiliation: Department of Pediatric Cardiology, Okinawa Children's Medical Center, Okinawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oginosawa
authors.affiliation: Department of Heart Rhythm Management, University of Occupational and Environment Health, Kitakyushu, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Maemura
authors.affiliation: Department of Pediatric Cardiology, Saitama International Medical Center, Hidaka, Japan.
authors.forename: Naokata
authors.initials: N
authors.lastname: Sumitomo
authors.affiliation: Sapporo Heart Center, Sapporo, Japan.
authors.forename: Kikuya
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.affiliation: Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.affiliation: Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: makitan@nagasaki-u.ac.jp.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D055815:Young Adult
keywords: Computer simulation; Meta-analysis; Mutation; Patch clamp; Short QT syndrome