title: Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study.
abstract: BACKGROUND
  Long QT syndrome (LQTS) can be caused by mutations in the cardiac ion channels. Compound mutations occur at a frequency of 4% to 11% among genotyped LQTS cases.
  
  
  OBJECTIVE
  The purpose of this study was to determine the clinical characteristics and manner of onset of cardiac events in Japanese patients with LQTS and compound mutations.
  
  
  METHODS
  Six hundred three genotyped LQTS patients (310 probands and 293 family members) were divided into two groups: those with a single mutation (n = 568) and those with two mutations (n = 35). Clinical phenotypes were compared between the two groups.
  
  
  RESULTS
  Of 310 genotyped probands, 26 (8.4%) had two mutations in the same or different LQTS-related genes (compound mutations). Among the 603 LQTS patients, compound mutation carriers had significantly longer QTc interval (510 ± 56 ms vs 478± 53 ms, P = .001) and younger age at onset of cardiac events (10 ± 8 years vs 18 ± 16 years, P = .043) than did single mutation carriers. The incidence rate of cardiac events before age 40 years and use of beta-blocker therapy among compound mutation carriers also were different than in single mutation carriers. Subgroup analysis showed more cardiac events in LQTS type 1 (LQT1) and type 2 (LQT2) compound mutations compared to single LQT1 and LQT2 mutations.
  
  
  CONCLUSIONS
  Compound mutation carriers are associated with a more severe phenotype than single mutation carriers.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamagata
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
authors.forename: Takashi
authors.initials: T
authors.lastname: Noda
authors.forename: Aya
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001145:Arrhythmias, Cardiac / Q000209:etiology; D044466:Asian People; D002648:Child; D018572:Disease-Free Survival; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D005838:Genotype; D006323:Heart Arrest / Q000209:etiology; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics* / Q000401:mortality; D008297:Male; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics; D013575:Syncope / Q000209:etiology; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels