Review Diagnosis, management and therapeutic Heart: first published as 10.1136/heartjnl-2020-318259 on 26 May 2021. Downloaded from strategies for congenital long QT syndrome Arthur A M Wilde , Ahmad S Amin, Pieter G Postema Heart Centre, Department ABSTRACT Diagnosis of Cardiology, Amsterdam Congenital long QT syndrome (LQTS) is characterised The diagnosis of LQTS relies on the heart rate Universitair Medische Centra, Amsterdam, The Netherlands by heart rate corrected QT interval prolongation and corrected QT interval (QTc) and on a number of life- threatening arrhythmias, leading to syncope and other electrocardiographic parameters as well as Correspondence to sudden death. Variations in genes encoding for cardiac elements obtained by history taking (eg, symptoms Professor Arthur A M Wilde, ion channels, accessory ion channel subunits or proteins and family history). Together they form the LQTS Amsterdam Universitair modulating the function of the ion channel have been probability or Schwartz score, where a score of Medische Centra, Amsterdam, identified as disease-causing mutations in up to 75% of ≥3.5 points indicates a high probability of LQTS The Netherlands; 2 3 a. a. wilde@ amsterdamumc. nl all LQTS cases. Based on the underlying genetic defect, (figures 1 and 2). Genetic information is not LQTS has been subdivided into different subtypes. part of the Schwartz score but an individual with Received 25 January 2021 Growing insights into the genetic background and a pathogenic variant also fulfills the current diag- Revised 12 April 2021 pathophysiology of LQTS has led to the identification nostic criteria for LQTS.3 It is important to realise Accepted 3 May 2021 of genotype–phenotype relationships for the most that the QTc of individuals with pathogenic variants common genetic subtypes, the recognition of genetic and normal healthy controls significantly overlap, and non-genetic modifiers of phenotype, optimisation indicating that a single QTc will never be able to of risk stratification algorithms and the discovery of distinguish all non- LQTS ECGs from all LQTS gene-specific therapies in LQTS. Nevertheless, despite ECGs.4 5 It is also important to realise that there these great advancements in the LQTS field, large are different methods to measure the QT interval, gaps in knowledge still exist. For example, up to 25% which need different cut- off values, and that the of LQTS cases still remain genotype elusive, which formulas for heart rate correction are imperfect hampers proper identification of family members at and also result in different cut-off values.5 In addi- risk, and it is still largely unknown what determines the tion, although the U- wave can also be abnormal in large variability in disease severity, where even within LQTS patients, the U- wave should not be included one family an identical mutation causes malignant in the QT assessment.6 Based on ECGs of a large arrhythmias in some carriers, while in other carriers, the number of genotyped LQTS patients and their disease is clinically silent. In this review, we summarise family members not carrying the familial variant, the current evidence available on the diagnosis, clinical we designed an online calculator with information http://heart.bmj.com/ management and therapeutic strategies in LQTS. on the likelihood that LQTS is present based on We also discuss new scientific developments and the calculated QTc (https://www. qtcalculator.org). 5 areas of research, which are expected to increase our In the past years, additional tools to more reliably understanding of the complex genetic architecture assess LQTS on the ECG have been developed,7–9 in genotype-negative patients, lead to improved risk including the use of artificial intelligence in estab- stratification in asymptomatic mutation carriers and lishing the diagnosis.10 more targeted (gene-specific and even mutation-specific) therapies. on October 2, 2021 by guest. Protected copyright. Genotyping and genotype–phenotype INTRODUCTION correlations Congenital Long QT Syndrome (LQTS), as the In the last 25 years, 17 genes have been associ- name implies, is characterised by a prolonged QT ated with LQTS. However, a recent analysis, based interval on the ECG, in the absence of structural on an approach using gene and disease specific heart disease and external factors such as a variety metrics designed by the Clinical Genome Resource of drugs.1–3 LQTS was first described in the 1950s (ClinGen), reclassified a number of these genes to of the previous century, initially in a family with limited or disputed evidence.11 This approach left deafness (ie, Jervell and Lange- Nielsen syndrome). seven genes with definitive or strong evidence for A few years later, in the early 1960s, patients with causality (table 1).11 These remaining genes all a similar ECG abnormality but without deafness encode for ion channels involved in cardiac repo- were described (ie, Romano- Ward syndrome). larisation, their modulatory subunits or proteins © Author(s) (or their Although initially this disease was subdivided into regulating or modulating the function of ion chan- employer(s)) 2021. Re- use permitted under CC BY. these two entities, later in time the more general nels. A positive genotype result, which is obtained Published by BMJ. terminology LQTS was used, and more recently in up to 75% of individuals with a clear phenotype, (1995–1996), it became clear that, based on the is of importance because it significantly contrib- To cite: Wilde AAM, underlying genetic defect, a further subdivision utes to risk and different aspects of the treatment Amin AS, Postema PG. 2 3 Heart Epub ahead of into distinct subtypes is pertinent. The various strategy. print: [please include Day milestones in the over 60 years history of this Indeed, specific genotype–phenotype rela- Month Year]. doi:10.1136/ disease are nicely summarised in a recent personal tionships have been described for the three most heartjnl-2020-318259 review by Dr Schwartz.3 common subtypes: LQTS types 1, 2 and 3 (figure 3). Wilde AAM, et al. Heart 2021;0:1–7. doi:10.1136/heartjnl-2020-318259 1 Review Heart: first published as 10.1136/heartjnl-2020-318259 on 26 May 2021. Downloaded from Figure 2 Schematic flow chart for the diagnosis LQTS. Flow chart for the diagnosis of LQTS following the Heart Rhythm Society/European Heart Rhythm Association/Asian Pacific Heart Rhythm Society consensus document from 2013.3 The LQTS risk score (ie, the ‘Schwartz score’) is presented in figure 1. *QTc calculated by Bazett formula (QTc=QT/√RR). LQTS, long QT syndrome; QTc, corrected QT interval. potential prolongation results in early afterdepolarisations that at one instant reach threshold for subsequent fast sodium inward current and a trigger beat that then degenerates into fast Table 1 Classification of genetic evidence by the Clinical Genome Resource (ClinGen) for genes previously associated with LQTS Figure 1 Diagnostic criteria for long QT syndrome (LQTS) (the http://heart.bmj.com/ ‘Schwartz- score’). Definite LQTS is defined by an LQTS score ≥3.5 points, Gene Protein Level of evidence intermediate probability of LQTS by an LQTS score of <3.5 and >1 and a AKAP9 A kinase anchor protein 9 Disputed low probability of LQTS by ≤1 point. In the family history rows, the same ANK2 Ankyrin-2 Disputed family member cannot be counted in both categories. CACNA1C Calcium voltage-gated channel α1c Moderate subunit CALM1 Calmodulin-1 Definitive The first two subtypes (LQT1 and 2) are based on functional CALM2 Calmodulin-2 Definitive loss-of - function variants in the potassium channel genes KCNQ1 on October 2, 2021 by guest. Protected copyright. CALM3 Calmodulin-3 Definitive and KCNH2, respectively. These genes respectively encode for CAV3 Caveolin-3 Limited the slow and rapid delayed rectifier current IKs and IKr, and a smaller amplitude of this current leads to prolongation of the KCNE1 Potassium voltage-gated channel Disputed subfamily E regulatory subunit 1 QT interval (figure 4A–D). LQTS type 3 is based on gain-of - KCNE2 Potassium voltage-gated channel Disputed function variants in SCN5A, the gene encoding the fast inward subfamily E regulatory subunit 1 cardiac sodium current (I ). Gain of function relates to an Na KCNH2 Potassium voltage-gated channel Definitive increased amplitude of the late sodium inward current (during subfamily H member 2 the plateau phase), which will also lead to prolongation of the KCNJ2 Potassium voltage-gated channel Limited action potential (figure 4D). subfamily J member 2 The age of onset of arrhythmias is typically younger in LQT1 KCNJ5 Potassium voltage-gated channel Disputed patients and in particular LQT1 males are at risk, whereas most subfamily J member 5 LQT2 and LQT3 patients who become symptomatic experi- KCNQ1 Potassium voltage-gated channel Definitive ence their first symptoms around puberty and here particular subfamily Q member 2 females are at risk (figure 3). Also, the morphology of the SCN4B Sodium voltage-gated channel β Disputed ST- T segments is rather specific for the three subtypes, and the subunit 4 genotype can be accurately predicted with these characteristic SCN5A Sodium channel voltage-gated α Definitive features.12 13 Furthermore, each genotype also has specific trig- subunit 5 gers for arrhythmic events and rather specific electrocardio- SNTA1 Syntrophin α1 Disputed 14–16 graphic features of the onset of the arrhythmias (figure 3). TRDN Triadin Strong The arrhythmias in LQTS (figure 4F) originate from the last *See for more details ref 11. part of the ventricular action potential where severe action LQTs, long QT syndrome . 2 Wilde AAM, et al. Heart 2021;0:1–7. doi:10.1136/heartjnl-2020-318259 Review Heart: first published as 10.1136/heartjnl-2020-318259 on 26 May 2021. Downloaded from http://heart.bmj.com/ Figure 3 Genotype–phenotype relationship for the three most important subtypes, types 1, 2 and 3. See text for further explanation.