Short QT and atrial fibrillation: A KCNQ1 mutation–specific disease. Late follow-up in three unrelated children

Sarquella-Brugada, Geòrgia; Campuzano, Òscar; Iglesias, Anna; Grueso, J; Bradley, David J.; Kerst, Gunter; Shmorhun, Daniel; Brugada, Josép; Brugada, Ramón

doi:10.1016/j.hrcr.2015.02.005

Cited by 12 publications

(8 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Genetic publications have reported gain-of-function pathogenic mutations mainly in three different potassium channels such as KCNQ1, KCNH2, and KCNJ2 (Sarquella-Brugada et al, 2015 ). Patients with these mutations have shortened atrial and ventricular refractory periods and shortened QT intervals in ECG signal.…”

Section: Discussionmentioning

confidence: 99%

Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study

Jeong

Lim

2018

Front. Physiol.

View full text Add to dashboard Cite

The KCNQ1 S140G mutation, which is involved in IKs current, affects atrial fibrillation. However, little is known about its effect on the mechanical behavior of the heart. Therefore, we assessed the influence of the KCNQ1 S140G mutation on ventricular electrophysiological stability and mechanical pumping performance using a multi-scale model of cardiac electromechanics. An image-based electromechanical model was used to assess the effect on electrical propagation and arrhythmogenesis of the KCNQ1 S140G mutation. In addition, it was used to compare the mechanical response under the wild-type (WT) and S140G mutation conditions. The intracellular calcium transient obtained from the electrophysiological model was applied as an input parameter to a mechanical model to implement excitation–contraction coupling. The IKs current equation was modified to account for expression of the KCNQ1 S140G mutation, and it included a scaling factor (ϕ) for mutant expressivity. The WT and S140G mutation conditions were compared at the single-cell and three-dimensional (3D) tissue levels. The action potential duration (APD) was reduced by 60% by the augmented IKs current under the S140G mutation condition, which resulted in shorter QT interval. This reduced the 3D sinus rhythm wavelength by 60% and the sustained re-entry by 56%. However, pumping efficiency of mutant ventricles was superior in sinus rhythm condition. In addition, the shortened wavelength in cardiac tissue allowed a re-entrant circuit to form and increased the probability of sustaining ventricular tachycardia and ventricular fibrillation. In contrast, under the WT condition, a normal wavelength (20.8 cm) was unlikely to initiate and sustain re-entry in the cardiac tissue. Subsequently, the S140G mutant ventricles developed a higher dominant frequency distribution range (2.0–5.3 Hz) than the WT condition (2.8–3.7 Hz). In addition, stroke volume of mutant ventricles was reduced by 65% in sustained re-entry compared to the WT condition. In conclusion, signs of the S140G mutation might be difficult to identify in sinus rhythm even though the mutant ventricles show shortened QT interval. This suggests that the KCNQ1 S140G mutation increases the risk of death by sudden cardiac arrest. In addition, the KCNQ1 S140G mutation can induce ventricular arrhythmia and lessen ventricular contractility under re-entrant conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study

Jeong

Lim

2018

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…Functional studies showed an alteration in function [43]. Posterior studies confirmed the curious phenotype in patients carrying the same variant [44,45]. Considering all data, including in silico predictions (Table 2), p.(Val141Met) should be classified as Pathogenic for SQTS following ACMG/AMP recommendations (Table 1 and Table 3, Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants

Campuzano

Fernández-Falgueras

Lemus

et al. 2019

JCM

Self Cite

View full text Add to dashboard Cite

Short QT syndrome, one of the most lethal entities associated with sudden cardiac death, is a rare genetic disease characterized by short QT intervals detected by electrocardiogram. Several genetic variants are causally linked to the disease, but there has yet to be a comprehensive analysis of variants among patients with short QT syndrome. To fill this gap, we performed an exhaustive study of variants currently catalogued as deleterious in short QT syndrome according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Analysis of the 32 variants described in the literature determined that only nine (28.12%) have a conclusive pathogenic role. All definitively pathogenic variants are located in KCNQ1, KCNH2, or KCNJ2; three genes encoding potassium channels. Other variants located in genes encoding calcium or sodium channels are associated with electrical alterations concomitant with shortened QT intervals but do not guarantee a diagnosis of short QT syndrome. We recommend caution regarding previously reported variants classified as pathogenic. An exhaustive re-analysis is necessary to clarify the role of each variant before routinely translating genetic findings to the clinical setting.

show abstract

“…To date, there is no published data on CNV analysis on patients with SQTS. De novo variants in the KCNQ1 gene have been associated with a particular in utero phenotype with clinical diagnosis of AF with concomitant bradycardia and short QT interval [ 194 , 195 ]. Some researchers support the screening of SQTS in the pediatric population, given its high lethality and the benefits of early diagnosis in the prevention of SCD.…”

Section: Short Qt Syndromementioning

confidence: 99%

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

et al. 2022

Self Cite

View full text Add to dashboard Cite

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

show abstract

Short QT and atrial fibrillation: A KCNQ1 mutation–specific disease. Late follow-up in three unrelated children

Cited by 12 publications

References 32 publications

Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study

Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study

Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Contact Info

Product

Resources

About