Reclassification of Genetic Variants in Children with Long QT Syndrome

Westphal, Dominik S.; Burkard, Tobias; Moscu‐Gregor, Alexander; Gebauer, Roman; Hessling, Gabriele; Wolf, Cordula M.

doi:10.1055/s-0040-1705528

Cited by 3 publications

(4 citation statements)

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“…All participants were 18 years or younger at the time of diagnosis. Those who were lost to follow-up were censored at the time of their last contact; part of this patient cohort was included in a recent publication [21].…”

Section: Methodsmentioning

confidence: 99%

Genetic Diagnostics Contribute to the Risk Stratification for Major Arrhythmic Events in Pediatric Patients with Long QT Syndrome Type 1–3

et al. 2022

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Long QT syndrome (LQTS) is an inherited arrhythmic disorder associated with sudden cardiac death (SCD). This study aimed to identify the clinical and molecular genetic risk factors that contribute to major arrhythmic events (MAEs) in patients with genetically confirmed childhood onset LQTS 1–3. This study was a retrospective double-center study. An MAE was defined as the occurrence of SCD, aborted SCD, appropriate implantable cardioverter defibrillator discharge, or sustained ventricular tachycardia. During a median follow-up of 4.6 years (range 0.1–24.3 years), MAEs occurred in 18 (17.8%) of 101 patients diagnosed with LQTS at a median of 7.7 years (range 0.0–18.0 years) despite the use of beta-blockers in 91.6% of patients at the last follow-up. A multivariate analysis identified a genetic diagnosis of LQTS2 and LQTS3 and variants within the KCNH2 S5-loop-S6 pore region as independent risk factors for MAEs, independent of the QTc value or a history of syncope detected from a univariate analysis. MAEs occur frequently in childhood onset LQTS despite beta-blocker treatment. A detailed molecular genetic diagnosis can contribute to the arrhythmia risk stratification and optimize the use of preventive measures in this vulnerable patient population.

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Section: Methodsmentioning

confidence: 99%

Genetic Diagnostics Contribute to the Risk Stratification for Major Arrhythmic Events in Pediatric Patients with Long QT Syndrome Type 1–3

et al. 2022

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“…Intragenic risk evaluation has been realized for LQTS patients based on mutation type, location, and cellular function [29] . LQT1 patients with transmembrane-spanning are at greater risk of an LQT1-triggered cardiac event than patients with C-terminal region mutations [30] .…”

Section: Risk Stratificationmentioning

confidence: 99%

Clinical Advances in Congenital Long QT Syndrome

Zhang

2021

Cardiology Discovery

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Long QT syndrome is an inherited arrhythmia characterized by a prolonged QT interval and increased risk of life-threatening cardiac events, including arrhythmogenic syncope, seizures, and sudden cardiac death with a structurally normal heart. Since its first description in the 1950s, extensive researches allowed a better understanding of the cause and mechanisms of this disease, which improved our ability of early diagnosis, risk stratification, and precise therapy of these patients. This article provides an updated review of the clinical and molecular profiles of this potentially lethal inherited disorder and summarizes current knowledge regarding diagnosis, risk stratification, and therapy.

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“…To investigate the utility of our approach, the functional evidence level determined from this assay was applied to enhance the classification of 18 KCNH2 missense variants detected by Westphal et al in children with suspected LQTS. 10 Evidence of abnormal LoF was found for 14 missense variants (Figure 2A, yellow and brown circles and Table S3). Four variants were in the range of normal function (Table S3).…”

mentioning

confidence: 95%

“…Overall, the variants that were determined by our assay to have severe LoF were detected in individuals with a more severe clinical phenotype (measured by Schwartz score) and a more prolonged QTc, this is consistent with previous observations. 13,14 The variant classifications in Westphal et al 10 were revised by applying the level of functional evidence at the strength determined by the Z-scores (Table S3). Considering this additional evidence, the classification of one variant (p.Leu697His) was upgraded from VUS to likely pathogenic after PS3 was applied at strong level (Table S2).…”

mentioning

confidence: 99%

Clinical interpretation ofKCNH2variants using a robust PS3/BS3 functional patch clamp assay

Thomson,

Jiang,

Richardson

et al. 2023

Preprint

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SummaryLong QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch clamp assay to facilitate classification of missense variants inKCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z-scores; the number of standard deviations from the mean of the normalised current density of the set of benign variant controls. A Z-score of –2 defined the threshold for abnormal loss-of-function, which corresponds to 55% wild-type function. More extreme Z-scores were observed for variants with a greater loss-of-function effect. We propose that the Z-score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics (ACMG) variant classification framework. The validity of this approach was demonstrated using a series of 18KCNH2missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS1) and the length of the QTc interval.

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Reclassification of Genetic Variants in Children with Long QT Syndrome

Cited by 3 publications

References 0 publications

Genetic Diagnostics Contribute to the Risk Stratification for Major Arrhythmic Events in Pediatric Patients with Long QT Syndrome Type 1–3

Genetic Diagnostics Contribute to the Risk Stratification for Major Arrhythmic Events in Pediatric Patients with Long QT Syndrome Type 1–3

Clinical Advances in Congenital Long QT Syndrome

Clinical interpretation ofKCNH2variants using a robust PS3/BS3 functional patch clamp assay

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