The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R)

doi:10.1016/j.hrthm.2013.07.022

Heart Rhythm

Volume 10, Issue 10, October 2013, Pages 1500-1506

https://doi.org/10.1016/j.hrthm.2013.07.022 Get rights and content

Background

Long QT syndrome type 13 (LQT13) is caused by loss-of-function mutation in the KCNJ5-encoded cardiac G-protein-coupled inward rectifier potassium channel subtype 4 protein. The electrocardiographic (ECG) features of LQT13 are not described yet.

Objective

To describe for the first time in detail the phenotype-genotype relationship of the ECG and clinical features in patients with LQT13.

Methods

The 12-lead ECGs, 24-hour Holter recordings, and clinical information from KCNJ5-G387R mutation carriers of a fourth-generation Han Chinese family with LQT13 and a group of healthy Chinese individuals were analyzed.

Results

Compared with the analysis of the healthy group (n = 8), age- and sex-matched pair analysis revealed that the mutation carriers (n = 8) had ventricular repolarization abnormality results in the prolongation of corrected QT and QTpeak intervals (P < .01); greater combined measure of repolarization morphology (T-wave morphology combination score) based on asymmetry, flatness, and notch (P < .01); and reduced low frequency/high frequency ratio of heart rate variability (P < .01) as a reflection of cardiac autonomic imbalance. Mean heart rate, time domain parameters of heart rate variability, time interval from T-wave peak to T-wave end, and T-wave amplitude were similar.

Conclusions

This study demonstrates for the first time the ECG features of patients with LQT13. Our data suggest that QTpeak intervals and T-wave morphology combination score may be the better parameters than the corrected QT interval to predict the phenotype-genotype relationship in patients with LQT13.

Introduction

Congenital long QT syndrome (LQTS) is an inherited cardiac disease associated with a prolonged QT interval on the surface electrocardiogram (ECG) and arrhythmia-related syncope and sudden cardiac death.¹ Until now, mutations in 13 genes have been identified in hereditary LQTS,² with KCNJ5 being the most recent identified gene.³ The KCNJ5 gene encodes the G-protein-coupled inward rectifier potassium channel subtype 4 protein (Kir3.4, also called GIRK4) responsible for the acetylcholine/adenosine-induced potassium current, I_K,ACh (I_GIRK).

The cardiac I_K,ACh is formed by a heteromeric or homomeric complex of Kir3.1 (encoded by gene KCNJ3) and Kir3.4 subunits.⁴ The compound Kir3.1/3.4 channels are important for heart rate regulation. The vagal release of acetylcholine stimulates muscarinergic activation of an inhibitory G protein, which in turn opens the Kir3.1/3.4 channel and repolarizes or hyperpolarizes the sinus node and atrial cardiomyocytes by activating I_K,ACh.5, 6 It has been reported that Kir3.4 knockout mice have a modest resting tachycardia, an inability to regulate heart rate in response to parasympathetic stimulation, and a longer ventricular effective refractory period than do wild-type mice.⁶ Yet, the effect of the dysfunctional Kir3.4 channel on human heart rate regulation has not been described.

In patients with LQTS, abnormal ventricular repolarization leads to abnormalities of the QT interval, ST segment, and T waves on the surface ECG.⁷ Previous studies have shown that the ST segment and T-wave pattern phenotype vary with affected LQTS gene.⁸ The aim of this study was to describe for the first time in detail the phenotype-genotype relationship of the ECG and clinical features in patients with long QT syndrome type 13 (LQT13).

Section snippets

Study population

A Han Chinese family with LQT13 and the Kir3.4-G387R mutation was evaluated.³ A total of 12 mutation carriers (2 of them were clinically diagnosed as patients with LQT13 because of lack of blood samples) from the family were investigated for clinical history. For 12-lead ECG analysis, only 8 patients were available since 3 patients died before the study and 1 had a ventricular-inhibited pacemaker (VVI, ie, ventricle paced, ventricle sensed, and pacemaker inhibited in response to sensed beat)

Results

The diagnosis of this family with LQT13 began when the proband was presented to the doctor with recurrent syncope (since the age of 22 years), family history, the markedly prolonged corrected QT interval (QTc; 520 ms), and negative echocardiogram finding (according to the Schwartz criteria¹⁴).

Discussion

In the present study, we demonstrate that patients with LQT13 have mild but significant repolarization changes, commonly experience syncope, and have supraventricular arrhythmias.

Conclusions

The present study demonstrates for the first time the clinical and ECG features of patients with LQT13. The new findings from this study are that, different from other common LQTS, patients with LQT13 have only slight but significant repolarization changes including prolonged QT_peak interval, increased MCS, and decreased LF/HF ratio in HRV.

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: The first 3 authors contributed equally to this work.

: This work was supported by the Danish National Research Foundation, the Danish Heart Foundation (grants 11-04-R84-A3333-22660 and 12-04-R90-A3935-22739 to Dr Liang), the Danish Strategic Research Council, the Fraenkel Foundation, the Faculty Medical Research Council, and the W.W. Smith Charitable Trust.

: Dr Kanters and Dr Graff are inventors of a patent regarding T-wave morphology.

View full text

The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R)

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Results

Discussion

Conclusions

Am J Hum Genet

Neuron

J Am Coll Cardiol

Heart Rhythm

J Electrocardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Electrocardiol

Heart Rhythm

syndrome

JAMA

The genetic basis of long QT and short QT syndromes: a mutation update

Hum Mutat

The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins

Nature

Impaired parasympathetic heart rate control in mice with a reduction of functional G protein betagamma-subunits

Am J Physiol Heart Circ Physiol

Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism

Hypertension

Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline

J Clin Endocrinol Metab

The G-protein-gated atrial K⁺ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins