7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Pathophysiology and genetics : Michael J Ackerman, MD, PhD, Peter J Schwartz, MD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 03, 2022. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1,2]. The primary symptoms in patients with LQTS include syncope, seizures, aborted cardiac arrest, and SCD. LQTS is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia known as torsades de pointes (TdP) or "twisting of the points" ( waveform 2A-B) [3,4]. LQTS may be congenital or acquired [1,5]. Pathogenic variants in at least 17 LQTS-susceptibility genes have been identified thus far ( table 1 and figure 1) [5]. However, pathogenic variants in the three canonical genes, KCNQ1 (previously called KVLQT1, LQT1), KCNH2 (previously called HERG, LQT2), and SCN5A (LQT3), account for at least 75 to 80 percent of all LQTS, with disease- causative variants in the minor LQTS-susceptibility genes contributing only another 5 percent. Less than 15 to 20 percent of patients satisfying a robust clinical diagnosis of LQTS will have a negative, contemporary LQTS genetic test. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2) [6]. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 1/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate The pathophysiology and genetics of congenital LQTS will be reviewed here. Other aspects of LQTS are discussed separately: Congenital LQTS Clinical features (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".) Diagnosis (See "Congenital long QT syndrome: Diagnosis".) Treatment (See "Congenital long QT syndrome: Treatment".) LQTS genes (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)".) Acquired LQTS Causes (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Diagnosis and management (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) PATHOPHYSIOLOGY Although the relatively simple clinical definition of LQTS applies to both acquired and the variety of congenital forms, the pathophysiology of the disorder is complex, incompletely understood, and probably varies among patients. Two leading pathophysiologic hypotheses have emerged to explain commonly observed features of LQTS: Extensive and growing clinical and genetic evidence supports the importance of perturbations in cardiac ion channels, resulting in prolongation of the action potential ( figure 1). Based on these data, congenital LQTS is considered a disease of ion channels and is the most common "cardiac channelopathy." The observation that the immediate trigger for torsades de pointes (TdP) in the inherited form is often a sudden surge in sympathetic tone (a feature not seen in the acquired form) led to the hypothesis that the congenital LQTS may be caused by an imbalance in the sympathetic innervation of the heart. Perturbations in ion channels The established pathogenic basis for the vast majority of congenital LQTS involves perturbations in three critical ion channels of the heart. Loss-of- function mutations in the KCNQ1-encoded Kv7.1 potassium channel (phase 3 I ) and KCNH2- Ks encoded Kv11.1 potassium channels (phase 3 I ) cause prolongation in the action potential Kr duration at the cellular level and hence QT prolongation for at least two-thirds of all patients https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 2/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate with LQTS. Gain-of-function mutations in the SCN5A-encoded Nav1.5 sodium channel account for approximately 5 to 10 percent of LQTS; they prolong the action potential duration by accentuating the sodium channel's late current or its window current. This action potential prolongation at the ventricular cardiac cell level sets up the increased vulnerability for early afterdepolarizations (EADs) and triggered activity via re-entrant mechanisms, which then produces torsadogenic syncope, seizure, or worse. (See 'Prolonged repolarization and early afterdepolarizations' below.) The normal action potential An understanding of normal cardiac cell electrophysiology is required in order to fully appreciate the known perturbations in ion channels and their associated ion currents, and the electrophysiologic mechanisms that cause congenital LQTS. The normal action potential is composed of the following five phases, beginning with phase 4 ( figure 2 and movie 1). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Phase 4 (resting membrane potential) Phase 4 represents the normal diastolic resting membrane potential of myocardial cells. The resting membrane potential of myocardial ventricular cell membranes during diastole is approximately -85 to -90 mV, which largely represents the equilibrium membrane potential for potassium in healthy states. This occurs because of the inwardly rectifying potassium channel Kir2.1 (I current) that is K1 encoded by KCNJ2. Phase 0 (depolarization) Phase 0 occurs when the membrane potential reaches approximately -70 mV. A rapid inward flow of sodium ions (I ) through the fast Nav1.5 Na sodium channels (encoded by SCN5A) ensues and depolarizes the cell membrane. Inward current during phase 0 is also sustained by activation of L- and T-type calcium channels (I Ca- and I ). L Ca-T Phase 1 (initial repolarization) Phase 1 represents an initial repolarization after the overshoot of phase 0 and is caused by a transient outward potassium current (I ) from to1 the KCND3-encoded Kv4.3 potassium channels. Phase 2 (plateau phase) Phase 2 is called the plateau phase, because it represents an equilibrium between the inward calcium (I /Cav1.2 encoded by CACNA1C and I ) and Ca-L Ca-T late sodium (I ) currents and the outward potassium currents coming from the Kv7.1/I Na Ks (KCNQ1) and the Kv11.1/I (KCNH2) potassium channels. Kr Phase 3 (rapid repolarization) Phase 3 represents the rapid repolarization that occurs when the outward potassium currents dominate over the decaying inward calcium current. Repolarization is predominantly mediated by the aforementioned outward potassium https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 3/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate currents (I and I ). These channels open in response to depolarization and allow Ks Kr potassium to flow out of cells and repolarize the membrane potential toward its resting level, until activated KCNJ2-encoded Kir2.1 potassium channels (I ) drive and hold the K1 membrane potential around -90 mV. The QT interval on the surface ECG is determined by the activity of these channels. Prolonged repolarization and early afterdepolarizations Prolongation of the QT interval increases the probability for EADs. EADs are single or multiple oscillations of the membrane potential that can occur during phase 2 or 3 of the action potential ( figure 2). EADs occur in association with prolongation of the repolarization phase of the action potential. If occurring in phase 2 of the action potential, EADs are thought to be caused by increased inward current through L-type calcium channels [7] or through the sodium-calcium exchanger [8]. Depolarizing currents occurring late in phase 3 are thought to be due to inward currents through T-type calcium channels or sodium channels [9]. Pathologic prolongation of repolarization results most often from a decrease in the outward currents (LQT1 and LQT2) or increases in the sodium current (LQT3). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Triggered activity'.) Triggered activity Triggered responses or triggered activity are EADs that reach threshold potential, depolarize cell membranes, and result in additional action potentials. Propagation of these triggered responses produce ventricular premature depolarizations that may initiate LQTS' pathognomonic polymorphic ventricular tachycardia (VT), known as TdP, in susceptible individuals. EADs and triggered responses are particularly easy to induce in Purkinje fibers and M cells, a group of cells in the left ventricular free wall that have been identified as the site of EAD-induced triggered activity after exposure to drugs such as quinidine, sotalol, and erythromycin [10,11]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Common precipitants of early afterdepolarizations and triggered activity The development of EADs is potentiated by bradycardia, hypokalemia, hypomagnesemia, and a long list of medications. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Bradycardia Slow heart rates are associated with increased inactivation of the outward repolarizing potassium current and a reduction in the Na-K-ATPase pump outward current (3 Na out/2 K in = net outward positive current). Slow heart rates also enhance the activity of certain antiarrhythmic drugs on repolarization (ie, repolarization and the QT interval are more prolonged). This property is called reverse use dependence and can lead to ion fluxes that facilitate EADs and TdP. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 4/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Hypokalemia Low potassium levels lead to a decreased outward repolarizing current via reductions in electrogenic Na-K-ATPase pump activity and outward potassium channel activity. Role of sympathetic activity Evidence supporting the significance of sympathetic activity in LQTS includes observations on the impact of the stellate ganglia. The left cardiac sympathetic nerves (left stellate ganglion and first four thoracic ganglia) are quantitatively dominant in terms of release of norepinephrine in the heart compared with the right-sided sympathetic nerves. In addition, the left-sided cardiac sympathetic nerves innervate primarily the posterior and left part of the ventricles [12,13]. In addition, sympathetic stimulation can also facilitate the onset of ventricular arrhythmias, including triggered activity and early after depolarizations. Experimental studies have demonstrated that right stellectomy or stimulation of the left stellate ganglion both prolong the QT interval and alter T wave morphology in a manner that mimics the surface ECG found in patients with LQTS, including the induction of T wave alternans [14]. Antiadrenergic therapies, including beta blockers and left cardiac sympathetic denervation (LCSD), substantially reduce the risk of TdP in patients with LQTS. Whereas beta blockers have a modest effect on the QT interval, LCSD shortens it significantly in most patients [15]. (See "Congenital long QT syndrome: Treatment".) Dispersion of repolarization and re-entry Both the dispersion of repolarization and re-entry may be other potential mechanisms for the development of TdP. Dispersion of repolarization refers to an inhomogeneity in repolarization or recovery of excitability in a region of myocardium. A specific population of cells in the myocardium, called M cells, demonstrate marked prolongation of action potential duration in response to drugs such as quinidine, sotalol, and erythromycin [10,11]. Dispersion of repolarization could therefore occur in response to these drugs if the action potential is prolonged in M cells but not in the surrounding myocardium. The result is a functional block in the M cell region, providing the necessary milieu for the development of a reentrant arrhythmia [10]. Initiation and maintenance of torsades de pointes EADs and triggered activity are thought to be the most common initiating mechanism for the ventricular ectopy and TdP associated with long QT intervals [16,17]. Alterations in sympathetic activity and dispersion of repolarization probably contribute to the electrophysiologic milieu that facilitates malignant arrhythmias, at least in certain cases. TYPES OF CONGENITAL LQTS https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 5/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Pathogenic variants in at least 17 genes have been identified thus far in patients with congenital LQTS ( table 1 and figure 1) [5]. However, as clinical genetic testing evolves and the available data become more robust, some previously associated LQTS-susceptibility genes have been reclassified as having limited evidence or disputed evidence as LQTS-causative genes in terms of the strength of their disease-gene association [18]. Additionally, the classifications and nomenclature are evolving, with the historical naming convention (LQT followed by the next number in sequence) being replaced by more descriptive names [19,20]. LQTS-causative variants in the three canonical genes, KCNQ1 (LQT1; 35 to 40 percent), KCNH2 (LQT2; 25 to 30 percent), and SCN5A (LQT3; 5 to 10 percent), account for at least 75 to 80 percent of all LQTS, with pathogenic variants in the minor LQTS-susceptibility genes contributing another 5 percent. (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)".) The remaining 15 to 20 percent of patients with an established clinical diagnosis of congenital LQTS will not have an identifiable genetic cause following clinically indicated contemporary genetic testing, and they are referred to as having either genetically elusive LQTS or genotype negative LQTS. Canonical LQTS-causative genes Type 1 LQTS (LQT1) The first association between a chromosomal marker and congenital LQTS was identified by analysis of a Utah family with a high prevalence of this disorder [21]. Linkage was found between the LQTS phenotype and a marker on the short arm of chromosome 11. Investigators using positional cloning techniques identified the involved gene KvLQT1, which is now called KCNQ1 [22]. LQT1 accounts for up to 45 percent of cases of LQTS (35 to 40 percent in most countries and most cohorts) [23]. Most patients with LQT1 show paradoxical prolongation of the QT interval during an exercise stress test, especially during the recovery phase of the stress test, which can be used to unmask patients with electrocardiographically concealed LQT1 [24,25]. The protein product of KCNQ1 (Kv7.1 alpha-subunit), when coexpressed with the cardiac protein minK (IsK or beta-subunit, which is encoded by KCNE1), forms the slowly acting component of the outward-rectifying potassium current (I ) [26-28]. Suppression of I by loss-of-function Ks Ks variants in the KCNQ1 gene in the absence or presence of minK can be correlated with and likely underlie prolongation of human ventricular action potentials [29]. Pathogenic variants in the KCNE1-encoded minK (LQT5) produces a similar defect in I ( figure 3). Gain-of-function Ks variants in KCNQ1 have been associated with familial atrial fibrillation [30] and with the congenital short QT syndrome, designated as type 2 short QT syndrome or SQT2 [31]. (See https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 6/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Genetic factors' and "Short QT syndrome".) Many missense variants and some other types of loss-of-function variants have been identified in KCNQ1. The severity of the clinical features of LQT1 vary with the specific LQT1-causative variant [32]. In particular, disease-causative variants localizing to the transmembrane region are associated with more frequent cardiac events (syncope, aborted cardiac arrest, or sudden cardiac death) than those variants that reside in the C-terminal region (55 versus 21 percent) [33]. Variants close to A341V carry a higher risk for arrhythmic events [32]. For example, one particular LQT1 variant (KCNQ1 A341V) is associated with high clinical severity independent of ethnic origin [34]. In a study comparing 244 patients with A341V with 205 patients with non-A341V LQT1 variants at a median follow-up of approximately 30 years, patients with LQT1-A341V were significantly more likely to have cardiac events (75 versus 24 percent), were younger at first event (6 versus 11 years), and had a longer QTc (485 43 versus 465 38 ms). Also, other LQT1-causative variants in proximity to A341V have been associated with a higher risk of arrhythmic events [32]. Homozygous loss-of-function variants in KCNQ1 can cause the Jervell and Lange-Nielsen syndrome [35,36]. Hearing loss can also be induced by the loss of functional minK protein, which seems to disrupt the production of endolymph. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Congenital sensorineural deafness'.) Type 2 LQTS (LQT2) LQT2, which accounts for 25 to 40 percent of cases of congenital LQTS [23,37,38], is caused by loss-of-function variants in a different potassium channel gene, localized to chromosome 7 [39-41]. The disease-causative gene is called KCNH2 (formerly HERG), which encodes the Kv11.1 potassium channel that underlies the rapidly acting component of the outward-rectifying potassium current (I ) ( figure 3) [42-45]. This current is largely responsible Kr for repolarization and thus the QT interval duration. The KCNH2-encoded Kv11.1 channels have unique electrophysiologic features that may normally protect against early afterdepolarizations (EADs) [44]. Most of the drugs that cause acquired/drug-induced QT prolongation block these Kv11.1 channels. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) LQT2-causative variants span the entirety of the Kv11.1 channel [41,46]. In a study of 201 patients, those with pathogenic variants localizing to the pore region had a significantly greater risk of a cardiac event (74 percent, versus 35 percent with variants in the non-pore region) and sudden cardiac death (SCD) or aborted cardiac arrest (15 versus 6 percent); these manifestations occurred at an earlier age in the patients with pore-localizing variants [41]. Patients with a LQT2- causative variant in Kv11.1's pore had a significantly greater risk of a cardiac event at a QTc of https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 7/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate 500 ms (hazard ratio 11); each 10 ms change in the QTc above or below 500 ms increased or decreased the risk by 16 percent. In some reports, non-pore variants are more likely to be associated with torsades de pointes (TdP) in the presence of hypokalemia [46]. However, a malignant phenotype has been described in a family with a novel variant in the nonpore region [47]. In contrast to LQT2-associated loss-of-function variants in KCNH2, there are gain-of-function variants in KCNH2 that result in accentuated I activity. Patients with KCNH2 gain-of-function Kr variants are classified as SQT1. (See "Short QT syndrome".) Type 3 LQTS (LQT3) LQT3, which accounts for 5 to 10 percent of cases [23,37,38], is caused by pathogenic variants in the sodium channel gene (SCN5A) located on chromosome 3; many variants have been associated with LQT3 [48,49]. The LQT3-causative variants result in gain-of- function by either increasing the late sodium current (like one of the originally discovered in- frame deletions, DeltaKPQ), increasing the window current through biophysical alterations of the kinetics of activation or inactivation, or through both mechanisms. One of the most interesting variants in SCN5A is the missense mutation, E1784K, which demonstrates most clearly the phenomenon of host-dependent disease expressivity, as E1784K is not only the most common LQT3-associated variant published to date but also the single most common SCN5A variant associated with a completely different genetic arrhythmia syndrome known as Brugada syndrome [50,51]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) Similar to LQT1 and LQT2, sporadic (de novo) SCN5A variants have also been described in which neither parent had either the variant or a prolonged QT interval. In contrast to the heritable variants, one of these de novo variants resulted in a prolonged opening and early reopening of the sodium channel, and therefore a threefold prolongation of sodium current decay [52]. Pathogenic variants in SCN5A have been associated with sudden infant death syndrome, at least some of which are sporadic [53-55]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Sudden infant death syndrome'.) Other disease-causative variants in SCN5A Different genetic variants in SCN5A can also cause a variety of other cardiac abnormalities, including Brugada syndrome, a related disorder, the sudden unexpected nocturnal death syndrome, an isolated familial atrioventricular conduction defect, congenital sinus node dysfunction, and familial dilated cardiomyopathy with conduction defects and susceptibility to atrial fibrillation. In addition, some pathogenic variants are associated with both LQT3 and the Brugada syndrome, with or without a conduction block [56,57]. (See "Brugada syndrome: Clinical presentation, diagnosis, and evaluation".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 8/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate The differences in clinical manifestations are probably due to differences in the electrophysiologic abnormalities induced by the specific variants [58,59]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Genetics' and "Etiology of atrioventricular block", section on 'Familial disease' and "Genetics of dilated cardiomyopathy" and "Sinus node dysfunction: Epidemiology, etiology, and natural history", section on 'Childhood and familial disease' and "Approach to sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Brugada syndrome'.) Compound/multiple variant-mediated LQTS In different large series, 4.5 and 7.9 percent of unrelated individuals who were each the first in their families to be diagnosed with LQTS (probands) had two disease-causing variants [60,61]. This unexpectedly high incidence of compound variants could be a reflection of selection bias, since such individuals would be more likely to develop clinical disease. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Epidemiology'.) Consistent with this hypothesis is the observation that patients with multiple variants, compared with those with only one variant, have significantly longer QT intervals and are more likely to experience a life-threatening cardiac arrhythmia [61,62]. The presence of >1 pathogenic variant can also affect the success of genetic testing. (See 'Genetic testing' below.) Minor LQTS-susceptibility genes Since the discovery of the three canonical LQTS-causative genes in the 1980s and 1990s, up to 14 additional, albeit minor, LQTS-susceptibility genes have been discovered by either hypothesis-driven candidate gene research or genomic triangulation strategies using whole exome sequencing [19]. The LQTS genotypes stemming from these minor genes ( table 1) have been annotated in the past as LQT4-17. However, these subtypes are best described by their gene, such as CACNA1C-LQTS (instead of LQT8) and TRDN-LQTS (instead of LQT17). Some of these minor genetic subtypes converge upon the final common pathway of one of the canonical subtypes. For example, LQT5 (preferred name: KCNE1-LQTS) mimics LQT1, while CAV3-LQTS results in accentuation of the late sodium current akin to primary variants in SCN5A (LQT3). The most common of the minor LQTS-susceptibility genes is probably CACNA1C-mediated LQTS (previously called LQT8) [63]. Gain-of-function variants in CACNA1C-encoded Cav1.2 were first discovered in a complex multisystem disorder called Timothy syndrome, which included marked QT prolongation [64]. More recently, however, other CACNA1C variants have been associated with cardiac-only, autosomal dominant LQTS. https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 9/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Among all of the minor LQTS-susceptibility genes, the most penetrant ones have involved either autosomal dominant or sporadic de novo variants in one of the three CALM genes that encode the 100 percent identical 103 amino-acid-containing calmodulin proteins or homozygous/compound heterozygous, autosomal recessive inherited variants in TRDN-encoded triadin [65,66]. The CALM1-3-LQTS subtypes are referred to collectively as the calmodulinopathies, since the phenotype overlaps with not only LQTS but also catecholaminergic polymorphic ventricular tachycardia [67]. These are listed in an International Calmodulinopathy Registry [68]. Similarly, patients with autosomal recessive loss-of-function variants in TRDN are referred to as having Triadin Knockout Syndrome (TKOS) because of phenotypic overlap; there is an International TKOS Registry to enroll patients with this severe channelopathy [68]. Children with these severe forms of disease (calmodulinopathies and TKOS) continue to experience breakthrough cardiac events despite receiving optimal guideline-directed LQTS therapies. GENETIC TESTING Clinical genetic testing is standard of care to identify LQTS-causative variants in any patient for which a clinical diagnosis of LQTS is being contemplated [69-72]. However, such testing is subject to limitations given the complexity and heterogeneity of the disorder. It has been estimated that a specific LQTS-causative variant in one of the three canonical genes (KCNQ1, KCNH2, and SCN5A) will be identified in at least 75 to 80 percent of patients who express a robust phenotype consistent with the diagnosis of LQTS [23]. Approximately 4 percent of controls have a rare variant of uncertain significance (in KCNQ1, KCNH2, or SCN5A), which represents a lower point estimate for the potential false positive rate for genetic testing [73,74]. In a series of 541 unrelated patients from the Mayo Clinic, the overall yield of genetic testing was approximately 50 percent and correlated with clinical measures of disease severity [75]: The likelihood of identifying a pathogenic variant increased progressively with increasing QTc, ranging from 0 to 62 percent as the QTc increased from the lowest (<400 ms) to the highest (>480 ms) category. A clinical LQTS diagnostic tool that predicts the likelihood of LQTS, the Schwartz LQTS score, is derived from the QTc, symptoms, and family history [76]. Patients with a Schwartz LQTS score 4, suggesting a strong probability of LQTS, had a disease- causative variant identified more frequently than those with a score <4 (72 versus 44 percent). (See "Congenital long QT syndrome: Diagnosis", section on 'Diagnosis'.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 10/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate Additional information on the approach to a genetic test result is presented separately. (See "Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A)".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Genetic variants At least 17 congenital long QR syndrome (LQTS)-susceptibility genes have been identified ( table 1). (See 'Types of congenital LQTS' above.) LQT1, LQT2, and LQT3 account for approximately 75 to 80 percent of cases of congenital LQTS. The minor LQTS-susceptibility genes account for <5 percent of LQTS. Some are associated with distinct clinical syndromes (eg, CALM1-3-mediated LQTS is called calmodulinopathy; TRDN-mediated LQTS is triadin knockout syndrome [TKOS]). https://www.uptodate.com/contents/congenital-long-qt-syndrome-pathophysiology-and-genetics/print 11/31 7/6/23, 11:08 AM Congenital long QT syndrome: Pathophysiology and genetics - UpToDate LQT1 This accounts for up to 45 percent of cases of the LQTS and is caused by loss-of- function variants in the KCNQ1-encoded Kv7.1 potassium channel. Most patients show paradoxical prolongation of the QT interval during the recovery phase after treadmill stress testing, which can be used to unmask patients with otherwise electrocardiographically (ECG) concealed LQT1. Events triggered by exercise, particularly swimming, are characteristic of (but not specific for) LQT1. (See 'Type 1 LQTS (LQT1)' above.) LQT2 This accounts for 25 to 40 percent of cases of congenital LQTS and is caused by a variety of loss-of-function variants in the KCNH2-encoded Kv11.1 potassium channels. Intragenic risk stratification is possible; as an example, patients with LQT2-causative variants localizing to Kv11.1's pore have worse clinical outcomes than those with pathogenic variants localizing the channel's C-terminal region. LQT3 This accounts for 5 to 10 percent of cases and is caused by gain-of-function variants in the SCN5A-encoded Nav1.5 sodium channel. Events occurring at rest or during sleep are characteristic of (but not specific for) LQT3. (See 'Type 3 LQTS (LQT3)' above.) LQTS genetic testing This has been available clinically/commercially since 2004 in the United States, and LQTS genetic testing is a class I recommendation for any patient being considered to have LQTS to enable genotype-guided risk stratification and genotype- guided tailoring of therapy and to permit cascade variant-specific testing of the appropriate relatives. (See 'Genetic testing' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Moss AJ. Long QT Syndrome. JAMA 2003; 289:2041. 3. El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18:6. 4. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and torsades de pointes. Med Clin North Am 2001; 85:321. 5. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. 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