Genetics of Arrhythmias

An arrhythmia (also spelled arrythmia) is defined as an irregular heartbeat resulting from a problem with the rate or rhythm of the heartbeat. During an arrhythmia, the heart can beat too fast (a condition called tachycardia), too slow (a condition called bradycardia), or with an irregular rhythm.  

Arrhythmias can be caused by changes in heart tissue and activity or in the electrical signals that control the heartbeat. These changes can be a result of damage from disease, injury, or genetics. Symptoms can vary, some people may feel faint or dizzy and others may have difficulty breathing. 

If you have a family member with a heart condition, you may want to talk with your doctor about your risk. Keep reading to learn more about which types of heart arrhythmias are hereditary and what you can do about them. 

Are arrhythmias hereditary? 

Yes, arrhythmias can be hereditary, meaning the condition can be passed down from parent to child. Hereditary cardiac disorders have a prevalence of 3% in the population.¹ They are considered rare with incidences estimated in the range of 1 in 2,000 to <1 in 10,000 in the general population. However, they account for a large proportion of cases of sudden cardiac death in young people (<35years of age).² Many of these unexplained sudden deaths occur owing to genetic mutations in genes encoding ion channels or their regulatory proteins.³ 

Which heart arrhythmias are genetic? 

The main hereditary cardiac arrhythmias are Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), and short QT syndrome (SQTS). 

They share several features: an overall low prevalence, their diagnosis is not always simple and they have the potential to trigger life-threatening arrhythmias, therefore, can be fatal.⁴ 

Brugada syndrome 

Brugada syndrome can lead to arrhythmias or irregular heartbeats in the heart’s lower chambers (ventricles), leading to so-called ventricular arrhythmias. If untreated, these arrhythmias can cause fainting (syncope), seizures, difficulty breathing, or even sudden cardiac death. These complications typically occur when an affected person is resting or asleep. 

Rare variants in the SCN5A gene are found in ~20% of patients with Brugada syndrome.⁶ Rare variants have also been reported in an additional 21 genes, but SCN5A remains the only undisputed Brugada syndrome-related gene according to a systematic assessment by the ClinGen initiative.  

Catecholaminergic polymorphic ventricular tachycardia 

Catecholaminergic polymorphic ventricular tachycardia (CPVT) can lead to an irregular heartbeat (arrhythmia). CPVT can be triggered by physical activity or emotional stress resulting in an abnormally fast heartbeat called ventricular tachycardia. Episodes of ventricular tachycardia can cause light-headedness, dizziness, and fainting (syncope). These episodes typically begin in childhood. 

If untreated, an episode of ventricular tachycardia may cause the heart to stop beating (cardiac arrest), leading to sudden death. Researchers suspect that CPVT may be a significant cause of sudden death in children and young adults with a structurally normal heart. 

CPVT is commonly inherited in an autosomal dominant manner. In 65% of CPVT probands, the disorder is caused by a mutation in RYR2, resulting in CPVT type 1. A rarer form, CPVT2, is caused by recessive mutations in CASQ2 and is estimated to be present in 3–5% of patients with CPVT.⁷ Furthermore, mutations in ANK2, CALM1, CALM2, KCNJ2, TECLR and TRDN have been described in patients with CPVT.⁸ 

Long QT syndrome 

In long QT syndrome (LQTS), the heart’s electrical system takes longer than normal to recharge between beats. This delay, which can be seen on an electrocardiogram (ECG), is called a prolonged QT interval. These fast and irregular heartbeats can cause fainting and seizures. In severe cases, LQTS can even lead to sudden death. 

To date, a number of genes have been implicated in LQTS. Genetic testing for LQTS has a diagnostic yield of ~60–70%.⁹ Mutations in KCNQ1, KCNH2 and SCN5A cause LQTS type 1 (LQT1), LQT2 and LQT3, respectively. Together, these subtypes account for ~75% of the patients with LQTS who have been genotyped (30–35% with mutations in KCNQ1, 25–40% in KCNH2 and ~5–10% in SCN5A).¹⁰ About 5% to 10% of patients with LQTS have multiple mutations in these genes, and symptoms typically present at a younger age and with a more severe phenotype in these patients than in patients with a single mutation.¹¹  

Short QT syndrome 

In short QT syndrome, the heart muscle takes less time than usual to recharge between beats. This shorter interval, which can be seen on an electrocardiogram (ECG), is called a short QT interval.  

If untreated, the arrhythmia associated with short QT syndrome can lead to a variety of signs and symptoms, from dizziness and fainting (syncope) to cardiac arrest and sudden death. These signs and symptoms can occur any time from early infancy to old age. This condition may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies <1 year of age. However, some people with short QT syndrome never experience any health problems associated with the condition. 

SQTS is inherited as an autosomal dominant disorder. Mutations in three genes KCNH2, KCNQ1 and KCNJ2, have been implicated in the disorder and are associated with its subtypes SQT1, SQT2 and SQT3, respectively. The genetic testing diagnostic yield in SQTS is low (<15%) and each known gene accounts for <5% of the patients with SQTS.¹² 

What are the symptoms of hereditary arrhythmia? 

Symptoms can vary depending on the type and cause of the arrhythmia, ranging from no symptoms to sudden cardiac death. 

Common arrhythmia symptoms include: 

• Cardiac arrest 
• Dizziness  
• Fainting (syncope) 
• Light-headedness 
• Palpitations (feeling of a rapid or fluttering heartbeat) 
• Pounding in the chest 
• Shortness of breath (difficulty breathing) 
• Weakness or fatigue 

Depending on the type of arrhythmia, these symptoms can be triggered by exercise, emotional stress, or rest. 

How can hereditary arrhythmia be diagnosed? 

Diagnosis relies on electrocardiogram (ECG) morphology (at rest and under stress), medical history, family history, and genetic analyses, although a causative mutation cannot always be identified.² Cascade genetic testing of family members is recommended to identify at-risk individuals. In this case, genetic analysis can confirm mutations in commonly affected genes that have been identified in the family. 

We offer genetic testing for all those conditions, find out more information about our product portfolio here. 

How can hereditary arrhythmia be treated? 

Common management and treatment recommendations for arrhythmias include: 

• Exercise restrictions and lifestyle changes 
• Medication, including beta-blockers, quinidine, antihypertensive drugs, calcium channel blockers and anti-arrhythmic drugs 
• Pacemaker 
• Implantable cardioverter-defibrillator (ICD) 
• Catheter ablation 

References 

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[2] Inherited cardiac arrhythmias. Nat Rev Dis Primers 6, 59 (2020). doi: 10.1038/s41572-020-0202-0. https://www.nature.com/articles/s41572-020-0202-0

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[4] Schwartz PJ et al. Inherited cardiac arrhythmias. Nat Rev Dis Primers 6, 58 (2020). doi: 10.1038/s41572-020-0188-7. https://doi.org/10.1038/s41572-020-0188-7

[5] Offerhaus JA et al. Epidemiology of inherited arrhythmias. Nat Rev Cardiol 17, 205–215 (2020). doi: 10.1038/s41569-019-0266-2. https://www.nature.com/articles/s41569-019-0266-2

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[7] Ackerman MJ et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011 Aug;8(8):1308-39. doi: 10.1016/j.hrthm.2011.05.020. https://www.heartrhythmjournal.com/article/S1547-5271(11)00607-2/fulltext

[8] Lieve KV et al. Catecholaminergic Polymorphic Ventricular Tachycardia. Circ J. 2016 May 25;80(6):1285-91. doi: 10.1253/circj.CJ-16-0326. https://www.jstage.jst.go.jp/article/circj/80/6/80_CJ-16-0326/_article

[9] Hofman N et al. Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years’ experience. Circulation. 2013 Oct 1;128(14):1513-21. doi: 10.1161/CIRCULATIONAHA.112.000091. https://www.ahajournals.org/doi/10.1161/circulationaha.112.000091

[10] Tester DJ et al. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol. 2006 Feb 21;47(4):764-8. doi: 10.1016/j.jacc.2005.09.056. https://www.sciencedirect.com/science/article/pii/S0735109705028007

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