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Brugada Syndrome, Genetic Testing

Brugada syndrome is a rare, inherited cardiac arrhythmia disorder that can lead to potentially life-threatening ventricular arrhythmias, including ventricular fibrillation. It is characterized by specific abnormalities in the electrocardiogram (ECG) and an increased risk of sudden cardiac death. The worldwide prevalence estimate is 1 case per 2.000 population; however, it may vary depending on ethnicity and geographic region. In Asian and Middle Eastern countries, the prevalence is higher (1:270-625) than in Europe (1:10.000) and North America (1:20.000). The disease is more common in men than in women (with a sex ratio of 8:1). Usually, it appears during the third or fourth day of life.

Brugada syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Key features and aspects of Brugada Syndrome include:

  • Electrocardiogram (ECG) Abnormalities: The hallmark of Brugada Syndrome is a characteristic pattern on the ECG, often referred to as a "Brugada pattern." This pattern typically involves ST-segment elevation in the right precordial (chest) leads, specifically leads V1 to V3.
  • Increased Risk of Ventricular Arrhythmias: Individuals with Brugada Syndrome are at an increased risk of developing ventricular arrhythmias, particularly ventricular fibrillation. Ventricular fibrillation is a life-threatening rhythm disturbance that can lead to sudden cardiac death.
  • Symptoms: Some individuals with Brugada Syndrome may remain asymptomatic, while others may experience palpitations, fainting (syncope), or sudden cardiac arrest. The first symptom for some individuals may be sudden cardiac death.
  • Fever-Induced Episodes: The characteristic ECG pattern and symptoms of Brugada Syndrome can be unmasked or aggravated by fever. This phenomenon is known as a fever-induced or drug-induced Brugada pattern.
  • Avoidance of Triggers: Individuals with Brugada Syndrome are advised to avoid specific triggers that can induce arrhythmias, such as certain medications, fever-reducing drugs, and excessive alcohol intake.
  • Management: Management of Brugada Syndrome involves risk stratification to determine the need for implantable cardioverter-defibrillator (ICD) placement. An ICD can treat life-threatening ventricular arrhythmias by delivering an electric shock to restore normal rhythm. Due to the severe nature of Brugada Syndrome and the risk of sudden cardiac death, individuals diagnosed with the condition often require close monitoring and management by a cardiac electrophysiologist. The approach to treatment and risk stratification may vary based on individual clinical characteristics and family history. Genetic counseling is recommended for individuals with Brugada Syndrome and their families to understand the genetic basis, assess the risk for family members, and provide information about potential preventive measures.

Brugada Syndrome has a genetic basis and is often caused by gene mutations such as SCN5A, which encodes for a sodium channel protein in the heart. The inheritance pattern is typically autosomal dominant. This syndrome is now known to be heterogeneous, and more genes, such as KCND3, SCN3B, and CACNA1C, are implicated in its development.

Brugada syndrome is caused, at the molecular level, by an imbalance of the ionic currents in the heart channels and is, therefore, a channelopathy. Several mutations can affect the SCN5A and CACNA1C genes, which encode cardiac sodium and calcium channel subunits. Mutations in the SCN5A gene account for 30% of cases of Brugada syndrome.

One of the variants most frequently associated with the development of Brugada syndrome is the E1784K mutation in the SCN5A gene, also known as c.5350C>T, p. Glu1784Lys. This mutation changes the glutamic amino acid at position 1784 for a lysine, generating a dysfunctional cardiac sodium channel.

The c.845G>A (p.Arg282His) variant in the SNC5A gene is also quite common in patients with Brugada syndrome. It results from substituting an arginine for a histidine at codon 282, which causes a deleterious effect on sodium channel function. Furthermore, it has been shown that in the presence of the common polymorphism (H558R), it is possible that the harmful effect of the c.845G>A variant is lost, and the functionality of the protein in the channel is recovered. This explains why some people who carry the c.845GtA variant never manifest symptoms.

This test analyzes the 44 most frequent pathogenic mutations of the SCN5A gene.

With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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