title: Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1.
abstract: BACKGROUND
  In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent.
  
  
  OBJECTIVE
  The purpose of this study was to evaluate clinical differences between patients with nonsense mutations.
  
  
  METHODS
  The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used.
  
  
  RESULTS
  Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered.
  
  
  CONCLUSIONS
  Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes.
authors: Heart Research Follow-up Program, Division of Cardiology, University of Rochester Medical Center, Rochester, New York; Department of Cardiology, Gentofte Hospital, Hellerup, Denmark.
authors: Martin H
authors: MH
authors: Ruwald
authors: Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, New York.
authors: Xiaorong
authors: X
authors: Xu Parks
authors: Heart Research Follow-up Program, Division of Cardiology, University of Rochester Medical Center, Rochester, New York.
authors: Arthur J
authors: AJ
authors: Moss
authors: Heart Research Follow-up Program, Division of Cardiology, University of Rochester Medical Center, Rochester, New York.
authors: Wojciech
authors: W
authors: Zareba
authors: Heart Research Follow-up Program, Division of Cardiology, University of Rochester Medical Center, Rochester, New York.
authors: Jayson
authors: J
authors: Baman
authors: Heart Research Follow-up Program, Division of Cardiology, University of Rochester Medical Center, Rochester, New York.
authors: Scott
authors: S
authors: McNitt
authors: Department of Cardiology, Gentofte Hospital, Hellerup, Denmark; Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Jorgen K
authors: JK
authors: Kanters
authors: Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
authors: Wataru
authors: W
authors: Shimizu
authors: AMC Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Arthur A
authors: AA
authors: Wilde
authors: Department of Cardiology, Gentofte Hospital, Hellerup, Denmark.
authors: Christian
authors: C
authors: Jons
authors: Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, New York. Electronic address: coeli_lopes@urmc.rochester.edu.
authors: Coeli M
authors: CM
authors: Lopes
mesh_terms: D000293:Adolescent; D000328:Adult; D018389:Codon, Nonsense / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D006323:Heart Arrest / Q000235:genetics; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D029597:Romano-Ward Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D013575:Syncope / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: Aborted cardiac arrest; Cardiac events; Frameshift; Haploinsufficiency; LQT1; Mutations; Nonsense; Stop codon; Sudden cardiac death; Syncope