KCNQ1 S6 Mutations and Clinical Severity in Long QT Syndrome

Dec 16, 2021
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Authors:
Schwartz PJ, Moreno C, Kotta MC, et al.
Citation:
Mutation Location and IKs Regulation in the Arrhythmic Risk of Long QT Syndrome Type 1: The Importance of the KCNQ1 S6 Region. Eur Heart J 2021;46:4743-4755.
Summary By:
Thomas C. Crawford, MD, FACC

Quick Takes

  • Prior studies have shown the malignancy of KCNQ1-p.A341V mutations. In this study of 1,316 LQT1 patients, the authors showed that mutations in the neighboring regions of the S6 subunit confer intermediate risk of arrhythmic events.
  • The frequency of symptomatic patients was 73% for the p.A341V mutations, 43% for the neighboring regions, and 20% for all others.

Study Questions:

In individuals with long QT syndrome type 1 (LQT1), does knowing the mutations, which neighbor p.A341V in the S6 channel segment of the KCNQ1 gene, predict the adverse clinical course?

Methods:

Clinical and genetic data were obtained from 1,316 LQT1 patients with 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighboring mutations, and 900 other LQT1 subjects. S6 segment missense variant characteristics, particularly cyclic adenosine monophosphate (cAMP) stimulation responses, were analyzed by cellular electrophysiology.

Results:

p.A341-neighboring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (p < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighboring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; p < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighboring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighboring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.

Conclusions:

KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk.                                                   

Perspective:

LQT1 is caused by loss-of-function mutations in the KCNQ1 gene, affecting the slowly activating delayed-rectifier K+ current IKs. Previous studies of subjects with LQT1 showed that a mutation in the sixth transmembrane segment (S6) of KCNQ1, p.A341V, has a very high risk of malignant arrhythmic course. The authors of the current manuscript show that the mutations, which closely neighbor p.A341V, are associated with intermediate risk of early first cardiac event and signify a poorer cumulative survival than mutations from any other region of the Kv7.1 subunit. The present manuscript provides further refinement in risk stratification for LQT1 patients. LQT1 carriers of a mutation located in the S6 segment should be considered at higher risk and be treated more aggressively.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Prevention, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Lipid Metabolism

Keywords: Adenosine Monophosphate, Arrhythmias, Cardiac, Electrophysiology, Genetics, Heart Defects, Congenital, KCNQ1 Potassium Channel, Long QT Syndrome, Loss of Function Mutation, Mutation, Risk Assessment, Romano-Ward Syndrome, Secondary Prevention


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