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Estefanía Martínez-Barrios, José Cruzalegui, Sergi Cesar, Fredy Chipa, Elena Arbelo, Victoria Fiol, Josep Brugada, Georgia Sarquella-Brugada and Oscar Campuzano
Submitted: 01 July 2022Reviewed: 27 July 2022Published: 28 October 2022
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Short QT syndrome (SQTS) is an extremely rare inherited arrhythmogenic entity. Nowadays, less than 200 families affected worldwide have been reported. This syndrome is characterized by the presence of a short QT interval leading to malignant ventricular tachyarrhythmias, syncope and sudden cardiac death. It is one of the most lethal heart diseases in children and young adults. Both incomplete penetrance and variable expressivity are hallmarks of this entity, making it difficult to diagnose and manage. Currently, rare variants in nine genes have been associated with SQTS (CACNA1C, CACNA2D1, CACNB2, KCNH2, KCNJ2, KCNQ1, SLC22A5, SLC4A3 and SCN5A). However, only pathogenic variants in four genes (KCNH2, KCNQ1, KCNJ2 and SLC4A3) have been found to definitively cause SQTS. The remaining genes lack a clear association with the disease, making clinical interpretation of the variants challenging. The diagnostic yield of genetic tests is currently less than 30%, leaving most families clinically diagnosed with SQTS without a conclusive genetic diagnosis. We reviewed and updated the main genetic features of SQTS, as well as recent evidence on increasingly targeted treatment.
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain
José Cruzalegui
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain
Sergi Cesar
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain
Fredy Chipa
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain
Elena Arbelo
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, Spain
Victoria Fiol
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain
Josep Brugada
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Arrhythmias Unit, Hospital Clinic, University of Barcelona-IDIBAPS, Spain
Georgia Sarquella-Brugada*
Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain
Medical Science Department, School of Medicine, University of Girona, Spain
Oscar Campuzano*
Centro de Investigación Biomédica en Red. Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Medical Science Department, School of Medicine, University of Girona, Spain
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
*Address all correspondence to: oscar@brugada.org and georgia@brugada.org
1. Introduction
Short QT syndrome is a rare inherited cardiac channelopathy characterized by the presence of short QT intervals and a high risk of malignant arrhythmias in the context of a structurally normal heart. Described more than 20 years ago by Gussak et al. [1], it was not until 2004 when the first genetic variants associated with the disease were published in KCNH2 [2] KCNQ1 [3] and KCNJ2 [4], named SQT1, SQT2 and SQT3, respectively. Since then, pathogenic variants have been described in six other genes associated with the disease, however, due to the low number of cases and the lack of a correct genotype-phenotype correlation, it is difficult to confirm the definitive pathogenic role of these genes as cause of SQTS. We aim to update current advances in SQTS, especially focused on genetics.
Today, it is difficult to establish the real prevalence of SQTS in the population, mainly due to the rarity of the disease and its possible underdiagnosis. The estimated prevalence is less than 1/10.000 in adults and about 1/2.000 in children and adolescents [5, 6, 7, 8]. SQTS is potentially lethal for children in the first year of life, leading to a cardiac arrest rate close to 4%, making it one of the causes of sudden infant death syndrome (SIDS) [9].
SQTS is diagnosed by the presence of a QTc ≤ 340 ms, or a QTc ≤ 360 ms when one of the following clinical criteria is met: detection of a clearly pathogenic genetic variant in one of the genes associated with the disease, family history of SQTS, family history of syncope or sudden cardiac death (SCD) before 40 years of age or survival of a ventricular tachycardia (VT) /ventricular fibrillation (VF) episode in the absence of heart disease [10]. However, its diagnosis can be challenging due to the large variability of the QT interval in healthy subjects.
Resting ECG should be performed at a normal heart rate when SQTS is suspected [11]. In addition, a stress test could be useful and a slope of the QT/HR ratio of less than −0.9 ms/beat/min could help distinguish affected subjects from healthy individuals [12]. Some studies support that QTc values should be adjusted in each population according to factors such as sex and age, and assessed in conjunction with other ECG criteria [13, 14]. For instance, a recent study in children and young adults demonstrated that a QTcB <316 ms, J-Tpeak cB < 181 ms (corrected by using Bazett's formula) and the presence of early repolarization (ER) could be indicative of SQTS in patients younger than 20 years of age [15]. Tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) could be part of the clinical evaluation, as systolic function may also be impaired and patients may present a dispersion of contraction in myocardium [16]. In contrast, invasive electrophysiological study (EPS) with programmed ventricular pacing is not recommended for SCD risk stratification [10] .
SQTS is characterized by a short QT interval in the ECG, with an asymmetric and sharp T wave, especially in precordial leads. Short or absent ST segments and paroxysmal episodes of atrial or ventricular fibrillation (Figures 1 and 2). The most common symptoms are palpitations (30%), syncope (25%) and cardiac arrest (40%) [17]. Ventricular and atrial fibrillation is present in most patients [18]. Cardiac events usually occur in adrenergic situations (noise or exercise), although occasionally it can also occur at rest [19]. Despite no studies focused on diet, any food modifying significantly the potassium levels may affect the QT interval. Symptoms occur in all age groups, with an increasing rate of SCD between 14 and 40 years of age. The probability of presenting with SCD as the first symptom increases with age, reaching 41% at 40 years of age [5]. A slightly male predominance was suggested, but recent analysis showed that although males present syncope more frequently than females, they show a lower risk of arrhythmic events and/or SCD [20]. In addition, some studies suggest that genes located on the X chromosome may be involved in the regulation of the QTc interval [21].
Figure 1.
ECG taken from a 39-year-old patient with SQTS; QT interval: 310 ms, QTc: 355 ms (corrected by using Bazett's formula).
Figure 2.
ECG diagram and cellular ionic currents under normal conditions (A) and SQTS (B). Voltage-gated Na+ and K+ currents define the ventricular action potential and the QT interval of the ECG. The functional effect of IKs, IKr or IK1 gain-of-function or INa or CaL loss-of-function on the ventricular action potential results in the shortening of the action potential associated with SQTS.
Short QT syndrome occurs mainly in an autosomal dominant pattern of inheritance with high phenotypic and genetic heterogeneity. To date, potential deleterious rare variants located in nine genes (CACNA1C, CACNA2D1, CACNB2, KCNH2, KCNJ2, KCNQ1, SLC22A5, SLC4A3 and SCN5A) have been associated with SQTS (Table 1) [22]. However, only three genes (KCNH2, KCNQ1 and KCNJ2) have been shown to cause SQTS definitively so far, and the SLC4A3 gene presents moderate evidence [23]. The association of the other genes with SQTS remains controversial (Figure 3) [24].
SQTS
Prevalence
Genes
Effect of variant
Current affected
Phenotypic overlap
SQT1 SQT2 SQT3
<15% <5% <3%
KCNH2 KCNQ1 KCNJ2
GOF GOF GOF
IKr IKs IK1
LQTS, BrS LQTS LQTS, CPVT
SQT4 SQT5 SQT6 SQT7
<1% <1% <1% <1%
CACNA1C CACNB2 CACNA2D1 SCN5A
LOF LOF LOF LOF
Ica Ica Ica INa
LQTS, BrS LQTS, BrS LQTS, BrS LQTS, BrS
SQT8
<1%
SLC4A3
LOF
AE3
.
SQTS-mimic
<1%
SLC22A5
LOF
.
CDSP
Table 1.
Genes associated with Short QT Syndrome or Shorter than normal QT interval and its phenotypic overlap with the main arrhythmogenic syndromes.
Diagram of the overlap between the genes associated with the short QT syndrome (SQTS) and the main channelopathies: Brs: Brugada syndrome; LQTS: long QT syndrome and CPVT: catecholaminergic polymorphic ventricular tachycardia.
Pathogenic variants in the KCNH2, KCNQ1 and KCNJ2 genes are responsible for SQTS type 1, 2 and 3 respectively. These variants are usually of the gain-of-function type and generate prolonged K+ channel activation, accelerated cardiac repolarization with shorter refractory periods, resulting in the short QT phenotype [25].
The KCNH2 gene (ID: 3757) encodes a voltage-activated potassium channel belonging to the eag family, subfamily H, member 2 (Kv 11.1 α/hERG subunit). It mediates the rapidly activating component of the delayed rectifying potassium current in the heart (IKr) [26, 27, 28]. Gain-of-function hERG variants lead to abbreviated ventricular repolarization and SQTS; in contrast, loss-of-function hERG variants are responsible for Long QT Syndrome (LQTS). The pathogenic variants p.Thr618Ile and p.Asn588Lys are the most frequently associated with SQTS [29]. Several functional studies have demonstrated the pathophysiological role of these variants, and their contribution to the SQTS phenotype seems clear [30]. Although other rare variants in the KCHN2 gene associated with SQTS have been described, many of them require further functional or segregation studies to elucidate their definitive pathological role.
The KCNQ1 gene (ID: 3784), encodes a voltage-activated potassium channel (Kv7.1 α-subunit) required for repolarization. This protein can form complexes associated with MinK (the KCNE1 gene) and MiRP2 (the KCNE3 gene) proteins, both potassium channel. When associated with KCNE1, it forms the IKs current, and induces rapid activation of the potassium-selective outward current. It can also associate with the MiRP2 protein and other associated proteins to form the potassium channel [3, 31]. Deleterious variants in this gene are associated with SQT2 and account for less than 5% of SQTS cases. In addition, some de novo variants in the KCNQ1 gene have been associated with a particular phenotype in utero with clinical diagnosis of atrial fibrillation (AF), along with concomitant bradycardia and SQTS [32]. The rare variants p.Val141Met and p.Val307Leu have the clearest association with SQT2 to date [22], being potential targets for various therapeutic models. For example, functional and computational simulation studies identified channel-specific blockade of IK1 or IKs as a possible antiarrhythmic strategy in SQT2, depending on the identified deleterious variants (p.Val141Met and p.Val307Leu, respectively) [33, 34].
The KCNJ2 gene (ID: 37591) encodes the integral membrane protein and an inward rectifier-type potassium channel, subfamily J, Member 2 (Kir2.1 α-subunit). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it (IK1 current) [4, 35]. Currently, pathogenic variants with the most evidence of causality for SQT3 are the variants p.Asp172Asn and p.Glu299Val [36, 37]. The KCNJ2 gene has also been associated with other channelopathies, mainly catecholaminergic polymorphic ventricular tachycardia (CPVT) [38].
6.1 Gene moderately associated with SQTS
In 2017, the SLC4A3 gene (Solute Carrier Family 4 Member 3, ID: 6508) was associated with SQTS, presenting an unusual mechanism for the development of malignant arrhythmia. SLC4A3 encodes plasma membrane anion exchange protein 3 (AE3) and acts by mediating part of the Cl-/HCO3- exchange in cardiac myocytes. To date, only one rare variant in this gene has been identified in two families (p.Arg370His). This loss-of-function variant would cause an increase in pHi and a decrease in [Cl-]i, shortening the AP duration and reducing the QT interval [39]. This gene is associated with SQT type 8; however, further studies are needed to clarify the definitive role of this gene in SQTS.
6.2 Other genes associated with SQTS
Loss-of-function alterations in genes encoding different subunits of cardiac Ca2+ channels have been associated with SQTS syndrome with an autosomal dominant inheritance pattern, each accounting for less than 1% of all SQTS cases [40]. However, evidence-based review of this association (ClinGen) leaves the causation of SQTS by mutations in these genes currently in dispute [24].
The CACNA1C gene (ID: 775) encodes an alpha-1 subunit of a voltage-dependent calcium channel (calcium channel, voltage-dependent, L-type, alpha 1C subunit, Cav1.2 α subunit). Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. To date, all variants identified in CACNA1C decrease inward currents at early phases of cell repolarization (ICaL) and induce transmural and epicardial dispersion of repolarization, leading to a combined phenotype of SBr and short QTc interval [41]. Currently, more than 10 rare variants in the CACNA1C gene have been potentially associated with SQTS, so-called SQT4. However, there is insufficient evidence to establish a definitive association and further studies are needed [22]. Gain-of-function variants in this gene have also been associated with LQTS.
The CACNB2 gene (ID: 783) encodes a subunit of a voltage-dependent calcium channel protein, a member of the voltage-gated calcium channel superfamily (Cav1.2 β subunit). The beta subunit of voltage-dependent calcium channels contributes to the calcium channel function by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting. Only one rare variant in the CACNB2 gene has been associated with SQTS (p.Ser481Leu) to date, known as SQT5. This variant is also found to be associated with BrS [40].
The CACNA2D1 gene (ID: 781) encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex (Cav1.2 α2/δ1 subunit). The protein regulates calcium current density and activation/inactivation kinetics of the calcium channel (ICaL) [40]. Only one variant has been identified in this gene (p.Ser755Thr), but its high frequency in the Ashkenazi population and conflicting evidence refutes its pathogenic role in SQTS [24]. It is associated with the so-called SQTS type 6. This gene has also been associated with other channelopathies, mainly LQTS.
The SCN5A gene (ID: 6331) encodes the alpha subunit of the type 5 sodium channel (Nav1.5) that mediates voltage-dependent sodium ion permeability in the cardiomyocyte. So far, only a rare variant in the SCN5A gene (p.R689H) has been described to be associated with SQTS (called SQT7). Carriers of this variant show a characteristic BrS phenotype with concomitant shortened QT intervals, but without a conclusive clinical diagnosis of SQTS. Therefore, its association is in dispute.
6.3 Gene associated with a SQTS-mimic phenotype
The SLC22A5 gene (ID: 6584) encodes a high-affinity sodium ion-dependent carnitine transporter protein (Solute Carrier Family 22 Member 5). So far, only the pathogenic variant p.Phe17Leu has been associated with SQTS, following an autosomal recessive inheritance pattern [42]. However, because the short QT phenotype is reversible with carnitine supplementation, the association of this gene with SQTS remains inconclusive [24].
Due to the low number of cases reported worldwide, the real penetrance and incidence of SQTS is difficult to estimate. Although some pathogenic variants exhibit 100% penetrance, approximately 40% of patients may remain asymptomatic [29]. Current guidelines recommend the analysis of four genes: KCNH2, KCNQ1, KCNJ2 and SLC4A3, despite last gene need more conclusive data concerning definite role [23]. Despite controversial association data between calcium channel genes and SQTS, current guidelines recommend the analysis of CACNA1C, CACNA2D1 and CACNB2, frequently associated with BrS. Genetic diagnosis of SQTS has a diagnostic yield of less than 30% [43] with the KCNH2 gene as the most cost-effective option [10]. Familial genetic analysis is recommended, both to clarify the pathogenic role of newly identified variants and to identify family members at risk for SCD.
Risk stratification is the main current challenge in the clinical setting, especially in asymptomatic patients carrying a pathogenic genetic alteration. In addition, patients with QTc intervals ≤340 ms should be considered at higher risk for SCD, despite the fact that no conclusive results have been published so far. ICD implantation is the treatment of choice for all patients with SQTS, especially for those who have survived aborted cardiac arrest or who have had spontaneous sustained VT [44]. However, there is also a significant risk of device-related complications, mainly due to inappropriate shocks from the over detection of T waves (high and narrow) seen in SQTS. Drugs that prolong the QT interval (quinidine and sotalol) should be considered for all patients at risk for SQTS in both asymptomatic and symptomatic patients who do not have an ICD, especially in young children [43]. Quinidine is currently the agent of choice, since in patients with SQT1, in addition to prolonging the QT interval and ventricular refractory period, it leads to the normalization of ST segments and T waves and the prevention of VF induction. However, the personalized use of drugs aimed at the treatment of patients carrying certain types of variants is becoming increasingly common. A study on human-induced, pluripotent stem cell-derived cardiomyocytes demonstrated that in addition to quinidine, ivabradine, ajmaline and mexiletine may be drug candidates for preventing tachyarrhythmias in patients carrying the p.Asn588Lys variant in the KCNH2 gene [45]. In addition, modelling studies indicated that high-dose amiodarone may be a potential drug treatment for SQTS2, especially those patients carrying the p.Val307Leu variant in the KCNQ1 gene [46]. Recently, a study show that vernakalant (sodium and potassium channel blocker) can prolong action potential and reduce arrhythmias in human-induced pluripotent stem cell-derived cardiomyocytes from a patient diagnosed of SQTS type-1 due to p.Asn588Lys, suggesting an effective candidate drug for treating arrhythmias [47]. Although more studies are needed to confirm these findings, the development of personalized treatments for inherited arrhythmias is currently in expansion.
Currently, SQTS is still a relatively unknown disease. First described in 2000, the small number of families diagnosed with SQTS worldwide makes the establishment of a risk stratification scale difficult. Clarification of electrophysiological and clinical abnormalities associated with the disease and the genetic origin, has only been carried out in recent years. However, only four genes (KCNH2, KCNQ1, KCNJ2, SLC4A3) have been definitively associated with the disease and a comprehensive genetic analysis only identify the causative alteration in no more than 30% of diagnosed families. It is crucial to perform more genotype-phenotype analyses in diagnosed SQTS families as well as segregation studies and in vitro/ion vivo functional tests that will allow clarification of the pathophysiological mechanism involved this lethal arrhythmogenic syndrome. Survivors of SCD have a high recurrence rate of episodes, thus implantation of an ICD is recommended in this group of patients. The pharmacological approach may also be effective in some cases, especially in the pediatric population, and the use of personalized medicine is becoming increasingly feasible. Personalized clinical evaluation, genetic analysis and the adoption of effective therapeutic measures by specialists help to improve the evolution of diagnosed patients with an increasingly positive long-term outcome.
This work was supported by Obra Social “La Caixa Foundation” (LCF/PR/GN19/50320002). CIBERCV is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.
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Written By
Estefanía Martínez-Barrios, José Cruzalegui, Sergi Cesar, Fredy Chipa, Elena Arbelo, Victoria Fiol, Josep Brugada, Georgia Sarquella-Brugada and Oscar Campuzano
Submitted: 01 July 2022Reviewed: 27 July 2022Published: 28 October 2022
Open access peer-reviewed chapter
