Genetic Determinants of Inherited Cardiac Arrhythmias

Long QT Syndrome

Long QT syndrome (LQTS) is the most common inherited cardiac channelopathy and an important cause of arrhythmic syncope and sudden cardiac death in otherwise healthy young individuals.^2,11,12 It is characterized by delayed ventricular repolarization, manifesting as prolongation of the corrected QT (QTc) interval on electrocardiography and predisposing to early afterdepolarizations and polymorphic ventricular tachycardia, most commonly torsades de pointes.² Diagnosis is based on electrocardiographic (ECG) findings, clinical features, family history, and genetic testing. Current criteria include a persistently prolonged QTc without secondary causes, a Schwartz score ≥ 3.5, or identification of a pathogenic variant in an LQTS-associated gene. The estimated prevalence is approximately 1 in 2,000 individuals.^2,11

At the molecular level, LQTS results from pathogenic variants in genes encoding cardiac ion channels or their regulatory proteins, disrupting the balance of ionic currents that govern ventricular repolarization. Most cases follow an autosomal dominant inheritance pattern, although rare recessive forms such as Jervell and Lange-Nielsen syndrome also occur. While several genes have been associated with the disease, approximately 70% to 80% of genetically confirmed cases involve three major genes: KCNQ1, KCNH2, and SCN5A.² KCNQ1 variants (between 40% to 55%) cause LQTS type 1 (LQT1) by reducing the slow delayed rectifier potassium current. KCNH2 variants impair the rapid delayed rectifier potassium current, producing LQT2, whereas gain-of-function variants in SCN5A increase the late sodium current, causing LQT3.²

Genotype-phenotype correlations in LQTS have important implications for risk stratification and management. In LQT1, arrhythmic events are typically, but not exclusively, triggered by adrenergic stimulation during exercise, particularly swimming. LQT2 events are often precipitated by sudden emotional stress or auditory stimuli such as alarm clocks. In contrast, LQT3 events occur predominantly during rest or sleep when sympathetic tone is low.^12,13,14 These genotype-specific triggers reflect distinct electrophysiological mechanisms associated with each ion channel defect and guide clinical management. Avoidance of QT-prolonging medications and recognition of genotype-specific triggers are therefore key components of preventive care.^2,14

Management of LQTS has increasingly shifted toward genotype-guided therapy and individualized risk assessment. The 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death recommend β-blockers as first-line therapy for most patients with congenital LQTS, including many asymptomatic individuals with a pathogenic variant.¹ Nonselective agents such as nadolol or propranolol are preferred because of their greater efficacy in suppressing adrenergically mediated arrhythmias, particularly in LQT1 and LQT2.¹ In LQT3, sodium channel blockers such as mexiletine may be considered to reduce the late sodium current and shorten the QT interval.¹ Implantable cardioverter-defibrillators are recommended for survivors of cardiac arrest and may be considered in high-risk patients with recurrent events despite therapy. Left cardiac sympathetic denervation and cascade genetic screening of relatives are also important components of management.^1,2,4

Brugada Syndrome

Brugada syndrome (BrS) is an inherited arrhythmia characterized by a distinctive electrocardiographic pattern of coved ST-segment elevation in the right precordial leads (V1-V3) and an increased risk of ventricular fibrillation and sudden cardiac death in individuals without structural heart disease.¹⁵ The diagnostic type 1 Brugada pattern shows ≥ 2 mm of coved ST-segment elevation followed by a negative T wave in at least one right precordial lead (V1-V3) recorded in the second to fourth intercostal spaces. This pattern may occur spontaneously or be unmasked by sodium channel-blocking drugs such as ajmaline or flecainide.¹⁵ BrS typically presents in adulthood, shows marked male predominance, and often manifests during rest or sleep. Prevalence is estimated at 1 to 5 per 10,000 individuals, with higher rates in Southeast Asia.^15,16

At the molecular level, BrS is primarily a cardiac sodium channelopathy. Loss-of-function variants in SCN5A, which encodes the α-subunit of the cardiac sodium channel Nav1.5, are the most established genetic cause. These variants reduce the inward sodium current during the early phases of the cardiac action potential, promoting conduction slowing and increased transmural dispersion of repolarization in the right ventricular outflow tract.¹⁷ However, SCN5A variants account for only about 20% to 30% of clinically diagnosed cases, reflecting significant genetic heterogeneity. Additional candidate genes affecting sodium, calcium, or potassium channel function have been proposed, but the pathogenic role of many remains uncertain, and current guidelines recommend restricting clinical genetic testing to genes with strong evidence of disease association.^4,17

The clinical expression of Brugada syndrome is influenced not only by genetic factors but also by environmental and physiological triggers that modulate cardiac ion channel function. Fever is a major precipitating factor, as elevated body temperature can further reduce sodium channel activity, unmask the Brugada ECG pattern, or trigger ventricular arrhythmias. Certain medications, particularly sodium channel-blocking drugs, may also reveal the characteristic ECG pattern or increase arrhythmic risk. In addition, increased vagal tone likely contributes to the nocturnal predominance of arrhythmic events. Recognition and management of these triggers are therefore essential in clinical care (Table 1).¹⁵

Management of Brugada syndrome focuses on risk stratification and prevention of malignant ventricular arrhythmias. The 2022 ESC guidelines recommend implantable cardioverter defibrillator (ICD) therapy for patients who have survived cardiac arrest or have documented ventricular arrhythmias. ICD implantation may also be considered in selected high-risk patients with syncope suspected to be arrhythmic and a spontaneous type 1 ECG pattern.¹ Asymptomatic individuals with a Brugada ECG pattern generally have lower risk. Current guidelines consider an electrophysiological study as an adjunctive tool that may be useful in risk-stratification and when decisions regarding ICD therapy are uncertain.^1,18,19 Fever should be treated promptly with antipyretics, and medications known to exacerbate the Brugada phenotype should be avoided.^1,15

Genetic testing plays a complementary role in the management of Brugada syndrome. Although its diagnostic yield is lower than in other inherited arrhythmia syndromes, identification of a pathogenic SCN5A variant can support the diagnosis and enable cascade screening of relatives. Screening of first-degree family members allows early identification of variant carriers and implementation of preventive measures, including clinical surveillance and counseling regarding avoidance of arrhythmia-triggering medications and conditions. Pharmacological therapy may also be considered in selected patients with recurrent ventricular arrhythmias or electrical storm or in those who reject ICD treatment. Quinidine, which inhibits the transient outward potassium current, can reduce arrhythmic events by restoring ionic balance during early repolarization.^1,20

Advances in invasive electrophysiological mapping have enabled substrate-guided catheter ablation strategies for Brugada syndrome, targeting abnormal epicardial regions in the right ventricular outflow tract thought to underlie the ECG pattern and arrhythmogenic substrate. Studies suggest that elimination of these abnormal electrograms can normalize the ECG pattern and reduce ventricular arrhythmia recurrence in selected high-risk patients.^21,22 Although currently reserved mainly for patients with recurrent ventricular fibrillation or electrical storm, these approaches illustrate the shift toward mechanism-based therapies and more individualized management of Brugada syndrome.

Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT is a rare but highly malignant inherited arrhythmia characterized by exercise- or stress-induced polymorphic or bidirectional ventricular tachycardia in individuals with structurally normal hearts and a normal resting electrocardiogram.^15,16,17,18 Arrhythmias typically occur during increased adrenergic stimulation, such as physical exertion or emotional stress, and may present with syncope, palpitations, or sudden cardiac arrest.^23,24,25,26 Symptoms usually appear in childhood or adolescence, although diagnosis may be delayed into adulthood. The estimated prevalence is approximately 1 in 10,000 individuals, though the condition is likely underdiagnosed due to a normal baseline ECG and absence of structural heart disease.

At the molecular level, CPVT results from abnormalities in intracellular calcium handling. Most cases are caused by autosomal dominant variants in RYR2, which encodes the cardiac ryanodine receptor responsible for calcium release from the sarcoplasmic reticulum during excitation-contraction coupling. These variants promote abnormal diastolic calcium leak, particularly during adrenergic stimulation. Less commonly, autosomal recessive variants in CASQ2, encoding calsequestrin-2, impair calcium buffering within the sarcoplasmic reticulum and disrupt calcium homeostasis. These defects lead to delayed afterdepolarizations and triggered activity that initiate polymorphic ventricular tachycardia during sympathetic activation. Additional rare variants in other calcium-handling proteins have been described but account for a small proportion of cases.²³

Diagnosis of CPVT is typically established by exercise testing or catecholamine provocation. During exercise, patients often develop progressive ventricular ectopy that may evolve from premature ventricular contractions to bidirectional or polymorphic ventricular tachycardia as heart rate increases. Genetic testing can confirm the diagnosis and is important for family screening, as mutation carriers may have a concealed clinical phenotype.^23,24

Management of CPVT focuses on suppressing adrenergically mediated arrhythmias and preventing sudden cardiac death. According to the 2022 ESC guidelines, nonselective β-blockers without intrinsic sympathomimetic activity—such as nadolol or propranolol—are recommended as first-line therapy for all patients.¹ In patients with persistent arrhythmias despite β-blockers, flecainide may be added since it suppresses abnormal calcium release from the ryanodine receptor and reduces arrhythmia burden.^1,25,26 Left cardiac sympathetic denervation may be considered in refractory cases, while ICDs are generally reserved for patients with recurrent cardiac arrest despite optimal therapy.^1,24

Genetic testing is central to management, enabling cascade screening of relatives and early identification of asymptomatic carriers who may benefit from preventive therapy and lifestyle modification (Table 1).^2,4,23

Calcium Release Deficiency Syndrome

In 2021, a new inherited arrhythmia syndrome was identified to be associated with loss-of-function mutations in the RYR2 gene. Unlike the gain-of-function RYR2 mutations seen in CPVT, which trigger exercise-induced arrhythmias detectable on exercise stress testing, individuals with calcium release deficiency syndrome (CRDS) can experience ventricular fibrillation or sudden cardiac death, with normal exercise tests, making the condition difficult to recognize.²⁷

The underlying mechanism involves impaired sarcoplasmic reticulum calcium release, leading to abnormal calcium handling, enhanced calcium alternans, prolonged action potentials, and a propensity for early afterdepolarizations rather than the delayed afterdepolarizations characteristic of CPVT. Invasive electrophysiologic testing with a well-defined protocol appears to be effective in unmasking the phenotype.

However, animal models have shown that not all RYR2 loss-of-function mutations cause the same CRDS phenotype. In mice carrying the RyR2-A4860G mutation, arrhythmias were triggered by an epinephrine-caffeine challenge, resembling the stress-induced pattern of CPVT, while the proposed CRDS diagnostic pacing protocol failed to reliably induce arrhythmias. These findings suggest that RYR2 loss-of-function mutations are heterogeneous, and that diagnostic tests and treatment strategies should be tailored to the specific mutation rather than assuming a single CRDS mechanism.²⁸

Current management relies on ICDs and antiarrhythmic agents such as flecainide, quinidine, and β-blockers, although larger studies are needed to establish optimal risk stratification and treatment strategies for this emerging ryanodinopathy.²⁹

Short QT Syndrome

Short QT syndrome (SQTS) is a rare inherited cardiac channelopathy characterized by abnormally shortened ventricular repolarization, reflected as a short QT interval on electrocardiography, and an increased risk of atrial and ventricular arrhythmias, including sudden cardiac death.^30,31,32 Although uncommon, SQTS is highly arrhythmogenic and may present with syncope, palpitations, atrial fibrillation, or sudden cardiac arrest, sometimes as the first manifestation of disease. Diagnosis is typically based on a markedly shortened corrected QT interval—generally ≤ 340 ms, or ≤ 360 ms with supportive clinical features such as a pathogenic variant, family history of SQTS, or documented ventricular arrhythmia.³² Clinical presentation may occur from childhood to adulthood.

At the molecular level, SQTS results from genetic variants that accelerate cardiac repolarization by increasing outward potassium currents or reducing inward depolarizing currents. Most cases are associated with gain-of-function variants in potassium channel genes such as KCNH2, KCNQ1, and KCNJ2, which enhance potassium efflux during repolarization and shorten the cardiac action potential and refractory period. Less commonly, loss-of-function variants in genes encoding L-type calcium channel subunits—such as CACNA1C, CACNB2, and CACNA2D1—reduce inward calcium current and produce a similar phenotype.^30,31,32 This abbreviation of the ventricular action potential promotes reentrant arrhythmias and increases susceptibility to atrial and ventricular fibrillation.^31,32

Management of SQTS focuses on preventing sudden cardiac death through risk stratification and arrhythmia suppression. According to the 2022 ESC guidelines, ICD therapy is recommended for patients who have survived cardiac arrest or experienced sustained ventricular arrhythmias.¹ However, ICD therapy can be challenging because the short QT interval and prominent T waves may lead to inappropriate shocks due to T-wave oversensing. Consequently, pharmacological therapy may be considered as an adjunct or alternative in selected patients.

Among pharmacological therapies for SQTS, quinidine has shown the most consistent efficacy in prolonging the QT interval and suppressing ventricular arrhythmias by blocking the rapid delayed rectifier potassium current.^1,31 Other antiarrhythmic drugs have demonstrated variable effectiveness, and available evidence is limited to small observational studies due to the rarity of the condition.

Genetic testing can support the diagnosis and facilitate family screening, although its diagnostic yield is relatively modest compared with other inherited channelopathies.^4,30 Identification of a pathogenic variant helps confirm borderline cases and enables cascade screening of relatives, allowing early detection and preventive monitoring of asymptomatic carriers.

Familial Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and is associated with increased risks of stroke, heart failure, and mortality.³³ While traditional risk factors include aging, hypertension, obesity, and structural heart disease, genetic predisposition also contributes significantly to AF susceptibility.³⁵ This genetic influence is particularly evident in early-onset AF, typically defined as occurring before age 60 and often in the absence of structural heart disease.^{6,7,8,9,10,35} Evidence from familial studies, twin studies, and genome-wide association studies indicates that both rare monogenic variants and polygenic susceptibility contribute to AF development, with most cases resulting from the cumulative effects of multiple common variants.^{6,7,8,9,10,35}

Among genetic loci associated with AF, variants near the transcription factor gene PITX2 represent the most consistently replicated and strongest genome-wide association study signal. PITX2 plays a key role in cardiac development, particularly in establishing left-right asymmetry and regulating electrical patterning of the left atrium and pulmonary veins—structures central to AF initiation.⁷ Reduced PITX2 expression has been linked to atrial electrical remodeling and increased arrhythmia susceptibility. In addition, variants in ion channel genes such as SCN5A, KCNQ1, and KCNE2 influence atrial depolarization and repolarization.^6,34 These alterations can disrupt atrial conduction and action potential duration, promoting reentry and triggered activity and highlighting overlap with inherited ventricular arrhythmia syndromes.

Beyond ion channel dysfunction, several additional genetic mechanisms contribute to AF susceptibility. Rare variants in natriuretic peptide A, encoding atrial natriuretic peptide, have been linked to familial AF and may promote atrial remodeling through effects on myocardial stretch, fibrosis, and neurohormonal signaling. Variants affecting intracellular calcium handling, including those involving ryanodine receptor pathways, may also promote abnormal calcium cycling and triggered activity. In addition, genes involved in intercellular coupling—such as GJA5 (connexin 40)—and proteins regulating cytoskeletal structure have been implicated in AF pathogenesis.^6,8,9 Disruption of these pathways can impair atrial conduction and promote the formation of reentrant circuits (Table 2).

Recent genomic studies have highlighted the importance of polygenic susceptibility in AF. Large genome-wide association studies have identified more than 100 loci associated with AF risk, many involving genes related to cardiac development, ion channel function, and structural remodeling.^9,10 Polygenic risk scores integrating these loci show promise for identifying individuals at increased genetic risk, particularly when combined with clinical factors. Although their clinical application remains under investigation, these findings emphasize the complex genetic architecture of AF and the interaction between genetic predisposition and acquired risk factors. Genetic testing is therefore mainly considered in selected cases such as early-onset or familial AF.^6,33