Inherited arrhythmia disorders are a group of hereditary conditions in which individuals have an abnormal heart rhythm known as an arrhythmia. Arrhythmias may be classified based on whether they originate in the atria or the ventricles and whether the heart rate is increased (tachycardia), decreased (bradycardia), or irregular. Clinical presentations are variable, with some individuals having no symptoms and others exhibiting severe symptoms (Kim et al., 2021). Many of these conditions are potentially life-threatening. Diagnosis may be guided by clinical history, electrocardiogram (ECG) findings, and family history. Management is condition-specific and may include medications or surgical interventions (Kim et al., 2021). Specific inherited arrhythmia disorders are described below:

Long QT syndrome

Long QT syndrome (LQTS) is characterized by abnormally prolonged QT intervals on ECG. LQTS may be diagnosed when the prolongation of the QTc interval is >470 msec (males) or >480 msec (females) (Groffen et al., 2003; Crotti et al., 2008). LQTS is a channelopathy, as it is caused by defects in the cardiac ion channels. Some individuals with LQTS are asymptomatic, but others may have symptoms including ventricular tachycardia (specifically torsades de pointes), dizziness, syncope, and cardiac arrest or sudden cardiac death. 

Individuals may have transient prolonged QT intervals from acquired causes such as electrolyte imbalance, head trauma or normalization of neonatal heart rhythms (Fernández-Falgueras et al., 2017). Inherited LQTS usually manifests before age 40, generally in childhood and adolescence depending on the genotype. At least 15 genes are associated with LQTS. The most common genes are KCNQ1 (30-35% of cases), KCNH2 (25-30%), and SCN5A (5-10%) (Groffen et al., 2003). The diagnostic yield of genetic testing approaches 85% (Fernández-Falgueras et al., 2017). LQTS is typically autosomal dominant, and de novo pathogenic/likely pathogenic (P/LP) variants are rare. Jervell-Lange-Nielsen syndrome, an autosomal recessive condition caused by biallelic P/LP variants in either KCNQ1 or KCNE1, is characterized by LQTS and severe congenital sensorineural deafness (Tranebjaerg et al., 2002).

Genetic testing is recommended for any patient who is strongly suspected to have LQTS if an acquired cause is unlikely. In addition, known familial variant testing is recommended for at-risk relatives, regardless of ECG findings, given the availability of prophylactic therapies (Ackerman et al., 2011; Musunuru et al., 2020). 

Long-term management of LQTS may include lifestyle modification, beta blockers, permanent pacemaker implantation, and implantable cardioverter defibrillators. Some common drugs, such as antibiotics, are known to increase the QT interval and should be avoided in patients with LQTS (Hickey and Elzomor, 2018). Genotype information may help target treatment. For example, propranolol with flecainide, ranolazine, and mexiletine seems to be more effective in patients with SCN5A P/LP variants, and nadolol is the only beta blocker that has been shown to successfully prevent arrhythmic episodes in patients with KCNH2 P/LP variants (Hickey and Elzomor, 2018). Mortality for patients with LQTS with appropriate medical therapy is now 0.3% (Wallace et al., 2019). 

Short QT syndrome

Short QT syndrome (SQTS) is characterized by abnormally short QT intervals on ECG (<360 ms) and an increased proclivity to develop atrial and/or ventricular tachyarrhythmias (Gussak et al., 2003; Gussack and Bjerregaard, 2005). Dizziness, syncope, or even sudden cardiac death can be the initial presenting symptom, but up to 40% of affected individuals may be asymptomatic (Campuzano et al., 2018). 

SQTS is inherited in an autosomal dominant manner. P/LP variants in four genes have been classified as having a moderate to definitive association with SQTS (KCNH2, KCNJ2, KCNQ1, and SLC4A3) (Wilde et al., 2022). Causative variants are found in less than 25% of affected individuals (Bjerregaard, 2018). Guidelines from the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Heart Rhythm Association/Heart Rhythm Association/Asia Pacific Heart Rhythm Association/Latin American Heart Rhythm Society state that SQTS genetic testing may be considered for any patient in whom a cardiologist has a strong clinical suspicion for SQTS based on clinical history, family history, and ECG. In addition, variant-specific genetic testing for at-risk relatives is recommended. (January et al., 2019; Priori et al., 2013; Wile et al., 2022). 

Management may involve implantation of a cardioverter defibrillator. The benefit of this in asymptomatic relatives is controversial (Bjerregaard, 2018). Quinidine has been shown to increase the QT interval in some cases, though its efficacy is still under investigation (Ackerman et al., 2011; Bjerregaard, 2018; Wilde et al., 2022). There is interest in establishing genotype-specific pharmacologic treatments, but these therapies are currently experimental (Hancox et al., 2018).

Catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare condition in which emotional or physical stress triggers catecholamine release, leading to arrhythmia and symptoms including dizziness, fainting, cardiac arrest, and even sudden death. The estimated prevalence of CPVT is 1 in 10,000, and symptoms tend to be earlier onset and more common among males than females (Fernández-Falgueras et al., 2017). The mean age of onset is between 7 and 12, but onset can occur as late as 40. Mortality from sudden cardiac death may be as high as 30% (Hickey and Elzomor, 2018).

Diagnostic findings can typically be identified on exercise ECG or in the setting of emotional stress. These findings include premature ventricular complexes, non-sustained ventricular tachycardia, and ventricular fibrillation. Genetic testing is required to confirm a diagnosis of CPVT (Hickey and Elzomor, 2018). 

RYR2 is the most common genetic cause of CPVT, with P/LP variants found in about 60% of individuals. Additional associated genes include KCNJ2, CALM1, CALM2, CALM3, TRDN, CASQ2 and ANK2 (Fernández-Falgueras et al., 2017; Baltogiannis et al., 2019). Most cases are inherited in an autosomal dominant manner; however, CASQ2 and TRDN P/LP variants are autosomal recessive. Guidelines from the Heart Rhythm Society recommend that at-risk relatives undergo familial variant-specific genetic testing. Beta blockers are suggested for those with P/LP variants, even if they have had negative ECG (Ackerman et al., 2011).

Brugada syndrome

Brugada syndrome (BrS) is associated with an increased risk of ventricular fibrillation and sudden cardiac death. It results from abnormal transport of sodium and potassium within cardiac cells. Symptoms may include chest discomfort, palpitations, nocturnal agonal respiration, and/or syncope, but patients may also be asymptomatic (Hickey and Elzomor, 2018). Symptoms often occur at rest and may be fatal if left untreated. Triggers include high fever, large meals, and excessive alcohol consumption. A diagnosis of BrS can be made based on ECG results and clinical history in approximately 75% of individuals. (Hickey and Elzomor, 2018). Genetic testing can also be helpful to make a diagnosis of BrS.

Implantable cardioverter defibrillators (ICDs) are the only therapy currently known to be effective in persons with BrS who have a history of syncope or cardiac arrest. ICD implantation is not indicated in asymptomatic BrS patients with drug-induced ECG findings (Priori et al., 2013). Avoidance of certain medications is recommended, as well as particular attention during febrile states as this can be a risk factor for syncope (Brugada et al., 2005; Hickey and Elzomor, 2018). 

P/LP variants in SCN5A account for more than 75% of cases in which a genetic etiology is identified. These variants are inherited in an autosomal dominant manner. According to guidelines from the Heart Rhythm Society, targeted testing of SCN5A can be useful to confirm BrS (Ackerman et al., 2011; Musunuru et al., 2020); however, there is limited evidence regarding the role of genetic test results in adjusting treatment, choosing medications or ICD implantation, or determining risk for complications (Juang and Horie., 2016; Wilde and Amin, 2017). In most cases, genetic testing for BrS primarily benefits at-risk relatives. Known familial variant testing is recommended for at-risk relatives. Genetic testing is not indicated among individuals with an isolated type 2 or 3 Brugada pattern on ECG (Ackerman et al., 2011).

More than 40 other genes have been associated with BrS, each individually accounting for less than 1% of cases (Brugada et al., 2005). Many of these genes have only been described in single patients or small families (Fernández-Falgueras et al., 2017). There is still significant ambiguity as to the exact gene involvement in most cases, and recent evidence suggests that BrS cases without SCN5A P/LP variants may frequently be oligogenic (Hickey and Elzomor, 2018; Wilde and Amin, 2017). Other studies have not found a significant association between variants in genes other than SCN5A and warn about interpretation of variants in such genes (Le Scouarnec et al., 2015; Hosseini et al., 2018). The data supporting pathogenicity is variable in part because many cases are sporadic and molecular mechanisms are difficult to elucidate. A review of data from the Human Gene Mutation Database concluded that a significant number of BrS-associated variants are not monogenic causes of BrS (Ghouse et al., 2017). 

Familial atrial fibrillation

Atrial fibrillation (AF) is characterized by uncoordinated electrical activity in the atria. Symptoms include dizziness, chest pain, palpitations, shortness of breath, syncope, and an increased risk of stroke and sudden death. Some individuals with AF are asymptomatic. Risk factors for AF include age, high blood pressure, and obesity (Kim et al., 2022). 

While the majority of AF cases are not hereditary, familial clustering does occur. One-fourth of individuals with AF have an affected first-degree relative (Choi et al., 2020). Familial cases of AF are clinically indistinguishable from acquired cases, and monogenic causes of AF have not been identified (Denti et al., 2018). Researchers have identified rare loss-of-function variants in the TTN gene that are associated with a significantly increased risk of early-onset AF. Despite this, major monogenic contributors to AF risk in the general population remain unclear (Choi et al 2020). Large-scale genome-wide association studies have identified at least 100 genetic loci with a potential association to familial AF (Choi et al., 2020; Campbell and Wehrens, 2018). There have been attempts to combine relative risk information from each individual single nucleotide polymorphism (SNP) into an overall genetic risk score. However, the role of risk assessment based on these common genetic variants is limited (Muse et al., 2018; Feghaly et al., 2018). Routine genetic testing related to AF is not recommended in guidelines from the American College of Cardiology, American Heart Association, and the Heart Rhythm Society (Ackerman et al., 2011; January et al., 2019). In a more recent statement, the American College of Cardiology and the American Heart Association Joint committee reiterated that the impact on clinical utiltiy of genetic testing for AF remains uncertain (Joglar et al., 2024). 

Atrioventricular block

Atrioventricular block (AV block) is a cardiac conduction disease that occurs when impulses from the sinoatrial node (SA node) are impaired as they travel to the ventricles of the heart. There are three types of AV block. Differentiation among these types is important given their different management requirements (Kashou et al., 2021). 

There are many causes of AV block including ischemia, infarction, medications, infection, and hypertension. In cases of congenital heart block, maternal immune response such as lupus is a known risk factor. Evidence is emerging that hereditary factors can also contribute to AV block. In studies of individuals with childhood incomplete AV block, two-thirds of those followed went on to develop complete AV block (Baruteau et al., 2012). Their presentation can be complex, with a wide QRS complex suggestive of diffuse disease. In addition, ECG findings differ between these children and their parents. It has been suggested that this is likely due to a complex interaction between multiple genes, consistent with the incomplete penetrance and variable expressivity seen in apparently familial AV block, channelopathies, and cardiomyopathies (Cannon and Ackerman, 2012).

Congenital complete AB block (CAVB) is often associated with maternal immune response. P/LP variants in the SCN5A and NKX2.5 genes have been identified in cases of CAVB, as well as other forms of cardiac disease. The prevalence of P/LP variants in these genes in those with CAVB is unknown. P/LP variants in the TRPM4 gene have been discovered in families with progressive cardiac conduction defects and may be responsible for an estimated 10% of cases of AV block (Kruse et al., 2009). 

Consensus guidelines from the Heart Rhythm Society, European Heart Rhythm Association, American Heart Association, and the American College of Cardiology recommend that genetic testing be considered for cardiac conduction diseases, especially when there is a family history. Although the positive predictive value of genetic testing is not high and results are unlikely to be clinically actionable, testing may be helpful in certain scenarios and is not expected to be harmful (Ackerman et al., 2011; Kusumoto et al., 2019).