Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1

TY - JOUR

T1 - Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1

AU - Ruwald, Martin H

AU - Xu Parks, Xiaorong

AU - Moss, Arthur J

AU - Zareba, Wojciech

AU - Baman, Jayson

AU - McNitt, Scott

AU - Kanters, Jorgen K

AU - Shimizu, Wataru

AU - Wilde, Arthur A

AU - Jons, Christian

AU - Lopes, Coeli M

N1 - Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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. Conclusion 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.

AB - 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. Conclusion 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.

U2 - 10.1016/j.hrthm.2015.08.033

DO - 10.1016/j.hrthm.2015.08.033

M3 - Journal article

C2 - 26318259

SN - 1547-5271

VL - 13

SP - 122

EP - 131

JO - Heart Rhythm

JF - Heart Rhythm

IS - 1

ER -