Long QT Syndrome: Genetics and Future Perspective

Pediatric Cardiology https://doi.org/10.1007/s00246-019-02151-x REVIEW ARTICLE Long QT Syndrome: Genetics and Future Perspective Eimear Wallace1 · Linda Howard1 · Min Liu1 · Timothy O’Brien1 · Deirdre Ward2 · Sanbing Shen1 · Terence Prendiville3 Received: 11 May 2019 / Accepted: 10 July 2019 © The Author(s) 2019 Abstract Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classically torsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnormal cellular membrane repolarization. Severely affected phenotypes administered current standard of care therapies may not be fully protected from the occurrence of cardiac arrhythmias. There are 17 different subtypes of LQTS associated with monogenic mutations of 15 autosomal dominant genes. It is now possible to model the various LQTS phenotypes through the generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes. RNA interference can silence or suppress the expression of mutant genes. Thus, RNA interference can be a potential therapeutic intervention that may be employed in LQTS to knock out mutant mRNAs which code for the defective proteins. CRISPR/Cas9 is a genome editing technology that offers great potential in elucidating gene function and a potential therapeutic strategy for monogenic disease. Further studies are required to determine whether CRISPR/Cas9 can be employed as an efficacious and safe rescue of the LQTS phenotype. Current progress has raised opportunities to generate in vitro human cardiomyocyte models for drug screening and to explore gene therapy through genome editing. Keywords Long QT syndrome · Arrhythmias · Cardiac · CRISPR–Cas systems · Gene editing · Induced pluripotent stem cells Introduction Long QT syndrome (LQTS), an inherited primary arrhythmia syndrome, demonstrates a prevalence of 1 out of every 2000 healthy live births [1, 2]. This cardiac ion channel repolarization abnormality manifests on the surface electrocardiogram (ECG), as a prolongation of the corrected QT interval, secondary to a delayed repolarization of the * Terence Prendiville 1 Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI) Galway, Galway, Ireland 2 Department of Cardiology, Tallaght University Hospital, Dublin, Ireland 3 Department of Paediatric Cardiology, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland cardiomyocyte action potential. This reduction in repolarization reserve places the cardiomyocytes at risk of propagating ventricular arrhythmia from early after depolarizations (EADs) that develop in phase two or three of the action potential [3]. These EADs are a product of the inherent dynamical chaos present in biological systems of cardiomyocytes. When small regions of myocardium develop EADs synchronously, it can trigger focal ventricular tachycardia that, if rapid enough, might result in vortex-like re-entrant excitation of the myocardium, Torsade de pointes (TdP). The clinical symptoms of LQTS include palpitations, syncope, and seizures, often due to adrenergic-induced TdP tachycardia [2]. A recessive form of the condition associated with deafness was first described in 1957 (by Jervell and LangeNielsen), and an autosomal dominant familial form by Dr. Romano in 1963 and Prof. Conor Ward in 1964. In 1985, Schwartz and Locati were the first to publish on the natural history of the disease and noted a 71% mortality rate in 13 Vol.:(0123456789) Pediatric Cardiology untreated patients from the first syncope [4]. Mortality in the current era for patients with LQTS with appropriate medical therapy is now 0.3% [5]. Genetics of LQTS LQTS has been classified into 17 subtypes (see Table 1) based on mutations associated with 15 autosomal dominant genes, LQT1-15 [6, 7]. LQT1 the most common subtype affects 30–35% of LQTS individuals and arises from the loss-of-function of KCNQ1 gene encoding the α-subunit of a voltage-gated potassium channel, KV7.1, expressed within the cell membrane of cardiomyocytes. K V7.1 mediates a slowly activating delayed rectifier potassium current (IKs). KV7.1 consists of four α-subunits which co-assemble with KCNE1 β-subunits to generate the IKs current. The KCNQ1 α-subunit has a voltage sensing domain (S1–4), a pore forming domain (S5–6), as well as intracellular N- and C-termini [8]. LQT1 manifests on the surface electrocardiogram as a broad-based and symmetrical T-wave with a prolonged QTc interval [9]. The incidence of life-threatening events is lowest for LQT1 compared to LQT2 or -3 [10]. Βeta-blockers are most effective in LQT1 at preventing breakthrough cardiac events [11]. At present, over 600 variants of KCNQ1 causing LQT1 have been described [12]. The location of a particular LQT1 mutation within the ion channel structure may be directly related to risk of cardiac event. The α-subunit is composed of an N-terminus, six membrane-spanning segments (S1–S6), two cytoplasmic loops (between S2–S3 and S4–S5), and the C-terminus portion. The presence of a mutation in the C-loop structure confers the highest risk for aborted cardiac arrest or sudden death [13]. The inverse correlate of this finding is that there may be a strategy to potentially avoid beta-blockers in low-risk individuals with LQT1 who do not harbor a C-loop mutation although this conclusion is somewhat controversial [14]. As shown in Fig. 1, physical exercise is the primary trigger for syncope or cardiac arrest in LQT1 [2]. LQT2 is the second most common subtype affecting 25–30% of LQTS individuals. hERG (human Ether-à-go-goRelated Gene) or KCNH2 codes for the voltage-gated pore forming α-subunit of the inwardly rectifying potassium channel subunit K V11.1. The KCNH2 α-subunits form a complex with KCNE2, a single transmembrane protein homologous to KCNE1, to generate the IKr current, intimately involved in membrane repolarization [8]. Heterozygote KCNH2 mutations exert a dominant-negative effect on wild-type hERG channel-associated IKr currents by impairing trafficking pathways or altered channel kinetics of the resulting co-assembled hERG heterotetramers [15]. LQT2 mutations within Table 1  Classification of genes responsible for cardiac channelopathies. Adapted from Schwartz et al. [2] LQTS type Gene Mutation frequency among LQTS population (%) Romano–Ward (RWS) LQT1 KCNQ1 40–55 LQT2 KCNH2 30–45 LQT3 SCN5A 5–10 LQT4 ANKB <1 LQT5 KCNE1 <1 LQT6 KCNE2 <1 LQT7 KCNJ2 <1 LQT8 CACNA1C <1 LQT9 CAV3 <1 LQT10 SCN4B <1 LQT11 AKAP9 <1 LQT12 SNTA1 <1 LQT13 KCNJ5 < (...truncated)