title: Novel KCNQ1 splicing mutation in patients with forme fruste LQT1 aggravated by hypokalemia.
abstract: BACKGROUND
  Several KCNQ1 splicing mutations have been identified in patients with type-1 long QT syndrome (LQT1). It was suggested that the clinical severity may differ according to the aberrant splicing products. There may be precipitating factors that cause cardiac events in those with a mild clinical phenotype (forme fruste LQT1).
  
  
  RESULTS
  We analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 31 consecutive LQTS patients. A novel KCNQ1 1251+1G>A (IVS9+1G>A) mutation was identified in three probands and their two relatives. The QT interval in all of the five individuals with mutation was not much prolonged in the absence of precipitating factors (mean QTc was 461±30ms.). Two of the five individuals with mutation were symptomatic. One patient (a 38-year-old female) had experienced recurrent episodes of syncope due to ventricular tachyarrhythmias (VTAs) accompanied by QT prolongation (QTc: 750ms) when the serum potassium concentration ([K(+)]) was 2.7mEq/L. After correction of [K(+)], the QTc interval was shortened to 515ms, and the occurrence of VTAs ceased. Another patient (a 22-year-old female) was resuscitated from cardio-pulmonary arrest due to VTAs. Just after resuscitation, the QTc interval was 629ms, and [K(+)] was 2.9mEq/L. After correction of [K(+)], the QTc interval was dramatically shortened to 440ms. In order to identify abnormal splicing products of the responsible mutation, we analyzed the reverse transcription-polymerase chain reaction products from peripheral bloods of the mutation carrier, and identified exon 9-skipping (Δ9) and cryptic sequential exons 8 and 9-skipping (Δ8-9) products, as well as a no exon-skipping product.
  
  
  CONCLUSIONS
  We identified a novel KCNQ splicing mutation 1251+1G>A in forme fruste LQT1, which induces cryptic splicing. Two of the five individuals with mutation experienced VTAs in the setting of hypokalemia, emphasizing the need to increase awareness of the significance of hypokalemia in this subgroup of LQT1 patients.
authors.affiliation: Department of Cardiovascular Medicine, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Imai
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Electronic address: tnakajim@med.gunma-u.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Cardiovascular Medicine, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan.
authors.forename: Nogiku
authors.initials: N
authors.lastname: Niwamae
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Irie
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ota
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iijima
authors.affiliation: Department of Cardiovascular Medicine, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Tange
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurabayashi
mesh_terms: D000293:Adolescent; D000328:Adult; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007008:Hypokalemia / Q000150:complications* / Q000235:genetics*; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029597:Romano-Ward Syndrome / Q000209:etiology* / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000209:etiology; D055815:Young Adult
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: Genetics; Potassium; QT syndrome-inherited; Ventricular arrhythmia