Brugada Syndrome (BrS) is a rare, inherited disorder of the heart’s electrical system that occurs in people with otherwise structurally normal hearts. This condition is classified as a channelopathy, meaning it is caused by a malfunction in the ion channels that regulate the heart’s electrical impulses. The syndrome significantly increases the risk of ventricular fibrillation, a life-threatening heart rhythm that can lead to cardiac arrest and sudden cardiac death, often occurring during rest or sleep. Understanding its inheritance pattern is the first step toward managing the risk for family members.
How the Syndrome is Inherited
Brugada Syndrome is most often transmitted through an Autosomal Dominant inheritance pattern. This means an individual only needs to inherit one copy of the altered gene from one parent to be at risk for the condition. The gene responsible is located on one of the non-sex chromosomes, which is what the term “autosomal” refers to.
For a person with the syndrome, there is a 50% chance that they will pass the genetic variant to their offspring. This risk applies equally to both male and female children, as the inheritance is not linked to the sex chromosomes. Although the majority of cases are inherited, the condition can also arise from a spontaneous de novo mutation, meaning the genetic change occurs in the affected person without being present in either parent.
Identifying the Genetic Culprit
The molecular foundation of Brugada Syndrome lies in the disruption of the heart’s ability to conduct electrical signals, a process governed by specialized ion channels. The most frequently identified genetic culprit is a variant in the SCN5A gene, which is found in approximately 20 to 30% of affected individuals. This gene contains the instructions for building the alpha-subunit of the NaV1.5 sodium channel, which is responsible for the rapid influx of sodium ions into heart muscle cells.
When a mutation occurs in SCN5A, it leads to a loss-of-function in the resulting sodium channel protein. This functional change reduces the amount of electrical current flowing into the heart cells, disrupting the initial phase of the heart’s action potential. This abnormality in the sodium current creates the distinctive electrical pattern seen on an electrocardiogram (ECG) and predisposes the individual to dangerous arrhythmias. While numerous other genes have been linked to BrS, SCN5A remains the most common and best-understood genetic marker for the condition.
Why Symptoms Vary Among Family Members
Despite inheriting the same genetic variant, family members often experience dramatically different clinical outcomes, a phenomenon known as variable penetrance. Penetrance describes the likelihood that a person who carries a specific gene mutation will actually show the symptoms or features of the associated disorder. For Brugada Syndrome, it is possible to carry the SCN5A mutation and never develop the characteristic abnormal ECG pattern or experience any symptoms.
This variability suggests that other factors—genetic, hormonal, or environmental—must interact with the primary mutation to cause the manifestation of the syndrome. Environmental triggers, such as a high fever, certain medications, or even a large meal, can temporarily unmask the condition by further stressing the already compromised sodium channels. Fever is a common trigger for life-threatening arrhythmias in individuals carrying a BrS mutation.
Screening for BrS in Relatives
Given the hereditary nature of Brugada Syndrome, screening is recommended for all first-degree relatives, which include parents, siblings, and children of an affected person. The initial screening involves a review of the family’s medical history and a standard 12-lead electrocardiogram (ECG). Because the abnormal ECG pattern can be transient, a single normal reading does not completely rule out the condition.
In cases where the diagnosis is uncertain, a physician may perform a sodium channel blocker challenge test. This involves administering a specific medication under controlled conditions to unmask the characteristic ECG pattern. Genetic testing for the SCN5A variant is also a routine part of screening, particularly when the causative mutation has already been identified in the family member with the syndrome. If a relative tests positive for the known familial mutation, they can be monitored closely and advised on lifestyle changes, such as avoiding certain drugs and aggressively treating fevers, which is a crucial step in preventing sudden cardiac events.