Observed genes

Polygenic score

Influential genes: SCN5A,SCN10A,ZFPM2,NCOA7,WT1-AS

Mutations in the SCN5A gene are the most common cause of Brugada syndrome.

Variants in the SCN10A gene have also been linked to Brugada syndrome, although it is a less common cause compared to SCN5A mutations.

ZFPM2 encodes a transcription factor involved in heart development, and mutations in this gene are related to Brugada syndrome.

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Overview

Brugada syndrome is a rare condition associated with specific ECG changes and a high risk of life-threatening cardiac arrhythmias. The Brugada brothers were the first to describe the syndrome in 1992 and since then the number of clinically diagnosed cases has grown rapidly. ⁽⁸⁾ However, the disease has been already known even before - in the Philippines as bangungut (to rise and moan in sleep), in Japan as pokkuri (sudden and unexpectedly ceased phenomena), and in Thailand as Lai Tai (death during sleep). ⁽⁸⁾ The recurrent theme of nocturnal episodes and sudden deaths in sleep is an accurate reflection of one of the common risk factors that can trigger clinical manifestations of the disease - the imbalance of the autonomic (sympathetic and parasympathetic) tone that can occur at rest, after a heavy meal or while a person is asleep. All these situations are associated with periods of higher parasympathetic and vagus nerve activity. ^{(6, 7)}

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The syndrome is an example of channelopathy, a disease characterized by a change in the flow of ions through the cell membrane. In the heart, this movement of particles (electrically charged particles of sodium, calcium, potassium, and chloride) through ion channels generates the cardiac action potential - an electrical signal, which propagates through the cells to induce a contraction of the heart - and is, therefore, the cornerstone of the heart’s electrical activity. The exact mechanisms that cause ECG changes and increase the risk of abnormal heart rhythms in Brugada syndrome are disputed and the subject of ongoing studies, however, most of them are thought to be accounted for by specific changes in sodium channels. In recent years, mutations in calcium and potassium channels and associated proteins have also been linked to the disease. ^{(1, 3, 6, 8)}

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Although the changes to the ECG might be present in an asymptomatic patient, they usually correspond to a high risk of cardiac arrhythmias, which include life-threatening ventricular tachycardia and ventricular fibrillation. The syndrome can also cause other arrhythmias such as conduction delay in the ventricles, atrial fibrillation, or atrioventricular block. ^{(1, 12)}  In a normal heart rhythm, electrical signals pass through the heart muscle at regular intervals. In fibrillation, the impulses propagate rapidly in a disorderly manner without any regularity. The consequence is that the relevant cardiac compartments lose their ability to pump blood effectively.

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Ventricular tachycardia (VT) is a rapid heart rate emanating from the lower chambers of the heart. Longer periods are particularly dangerous as they can easily progress to ventricular fibrillation and cardiac arrest.

Fig 1: Ventricular tachycardia | Mayo Clinic

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Ventricular fibrillation (VF) causes the ventricles to merely quiver instead of contracting, the heart is unable to pump blood at all, and cardiac arrest occurs. 

Fig 2: Ventricular fibrillation | Mayo Clinic

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Atrial fibrillation (AFib) causes an irregular, very rapid heart rhythm because the chaotic impulses from the atria are also transmitted with absolute irregularity (although at a lower frequency) to the ventricles. 

Fig 3: Atrial fibrillation | Mayo Clinic

Prevalence & Risk factors

The estimated worldwide prevalence of the disease is 1:2000. ⁽¹⁾  However, the prevalence of the disease varies depending on the location. In Thailand, for example, the prevalence is as high as 17.7 per 1000 inhabitants. ⁽¹²⁾ The average age of those affected is 41 years and the syndrome is more often diagnosed in men. More specifically, men are approximately 8 to 10 times more likely to be diagnosed with the syndrome, although the likelihood of inheriting a mutated gene does not vary depending on the sex of the individual. ⁽¹⁾  Thus, it is clear that the penetrance of the mutation (the probability of the gene variant manifesting itself clinically) is higher in males than in females. Brugada syndrome is also more common in people from Southeast Asia. Interestingly, studies also show that people suffering from schizophrenia are more likely to have a Brugada pattern on their ECG than the general population. ^{(1, 3, 6, 9)}

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General risk factors therefore include:

• Male gender ⁽⁷⁾
• Age ⁽⁷⁾
• Family history of the syndrome or SCD ⁽⁷⁾
• Asian race ⁽⁷⁾

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From what is known, ECG findings as well as clinical symptoms can be intermittent and they can be unmasked or augmented by multiple factors. These include:

• Ischaemia of the heart ⁽⁸⁾
• Autonomic tone changes (for example in sleep) ⁽⁷⁾ 
• Fever ⁽⁷⁾ 
• Cocaine or alcohol intoxication ⁽⁸⁾
• Certain medications, e.g. sodium channel blockers (Flecainide, Propafenone), calcium channel blockers, alpha agonists, beta-blockers, nitrates, cholinergic stimulants, and heterocyclic antidepressants ⁽⁸⁾
• Potassium levels (both hyper and hypokalemia) ⁽⁸⁾
• Hypothermia ⁽⁸⁾
• Cardioversion ⁽⁸⁾

Genetics

For many years, the syndrome was considered to be monogenic (determined by a single gene) with an autosomal dominant inheritance pattern (only one allele is enough to cause the disease). Nowadays, research suggests that the syndrome is of heterogeneous nature. 

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The very first gene associated with this syndrome was the SCN5A gene, which encodes for sodium channels in the heart. Changes affecting this gene are found in between 15-30% of cases, although the clinical manifestations vary in each person.^{(3, 12)} 

More than 300 mutations have been found in the SCN5A gene, each affecting its function in a different way, which may explain why this syndrome is benign in some people and life-threatening in others.⁽¹¹⁾ 

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In the last two decades, more than 20 additional genes (potentially causative) have been identified, most of them encoding sodium, potassium, and calcium channels or the associated proteins. ⁽¹²⁾

Overall, it is estimated that only 30–35% of patients can be genetically diagnosed, leaving 65–70% of patients undiscovered. ⁽¹³⁾

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That’s the reason why, here in Macromo, polygenic risk scores are used to determine genetic risk. The polygenic risk score (PRS) is an estimate of the probability that an individual carries a given trait based on genetics, without considering environmental factors. Variants across their genome are summed and weighted according to their effect on the disease or trait.

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Signs & Symptoms

Brugada syndrome usually first manifests in the third and fourth decades of life. Nonetheless, approximately 63% of patients have no symptoms apart from specific ECG findings at the time of diagnosis. Others may develop some of the following signs:

• Dizziness ⁽⁷⁾
• Loss of consciousness (syncope) ⁽⁴⁾
• Gasping or strenuous breathing, especially at night ⁽⁷⁾
• Palpitations ⁽⁷⁾
• Seizures ⁽⁷⁾
• Sudden cardiac arrest ⁽⁴⁾

Syncope or episodes of arrhythmia can occur at any age. Moreover, SCD may even represent the first symptom of the disease for some. Unfortunately, this also applies to children, where an association between Brugada syndrome and sudden infant death or SCD in children has been proven. ⁽¹²⁾

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Diagnosis

The diagnosis of Brugada syndrome is most often made after a person faints and seeks medical attention or survives a cardiac arrest. In some individuals, the diagnosis can be incidental during a routine medical examination because of the presence of specific ECG findings and the relevant family history of SCD or Brugada ECG patterns. However, both the pattern and clinical symptoms are needed to form a diagnosis. Without the presence of a typical pattern on the ECG, ventricular arrhythmias cannot be classified as Brugada syndrome. And correspondingly, even a characteristic pattern without clinical symptoms cannot be considered a Brugada syndrome, but only a Brugada pattern. ⁽⁴⁾

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To diagnose Brugada syndrome, several tests and methods may be used:

• Family and personal clinical history of cardiac diseases
• Physical examination
• ECG
• Stress testing (using specific medications)
• Echocardiogram
• Genetic testing
• Electrophysiology test (using a catheter to map out irregular heartbeats) 

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Therapy

The main goal of treatment is to reduce the risk of sudden death due to ventricular arrhythmias. The treatment depends on the risk of developing said arrhythmia because, for some, the syndrome can remain a benign condition. High-risk patients have:

• Personal history of ventricular arrhythmia ⁽⁷⁾
• History of unexplained syncope ⁽⁷⁾
• History of sudden cardiac arrest ⁽⁷⁾

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Prevention

Due to the heritability of the disease, it is always important to perform genetic testing on close relatives of patients with Brugada syndrome, as it is the best way to prevent the life-threatening events associated with genetic mutations. Once a person has been diagnosed with Brugada syndrome, it is important that they see their doctor regularly and follow their doctor's recommendations depending on their risk of heart arrhythmia. ⁽⁷⁾

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Prognosis

Studies show that the most important prognostic risk factor is a history of ventricular tachyarrhythmia leading to sudden cardiac arrest or syncope. Other less important factors include atrial fibrillation, male gender, and family history of SCA. ⁽⁵⁾ 

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Sadly, Brugada syndrome remains a notable cause of death, especially in men under 40 years of Southeast Asian descent. It is estimated that 4% of all sudden deaths (and at least 12-20% of sudden deaths in patients with structurally normal hearts) are due to this syndrome. The mean age of sudden death in patients with this syndrome is 41 ± 15 years. ^{(1, 10)}

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Recommendations

• If you experience any of these symptoms, consult your doctor to see if Brugada syndrome or another heart problem is causing the symptoms. 
• If you experience an unexplained loss of consciousness, always seek medical attention.
• If your immediate family has been diagnosed with Brugada syndrome, arrange to get tested to rule out an increased risk of malignant arrhythmias.

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