Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Scientific Background

Brugada syndrome (BrS) is one of the most common causes of sudden cardiac death and responsible for approx. 20–30% of all cases with a structurally normal heart. It is an autosomal dominant disease with incomplete penetrance. Worldwide the prevalence on average is 1 in 2,000 with 90% being male patients. Manifestation of the disease may be in early childhood; however, it is typical at the age of 30–40. Persistent ST elevations in the right precordial lead are characteristic ECG findings. In some cases they can only be unmasked by antiarrhythmic agents such as ajmaline or flecainide. BrS is associated with a disposition to rapid polymorphic ventricular tachycardia and ventricular fibrillation. Symptoms frequently occur at night and often result in sudden cardiac death. The risk of sudden cardiac death is 2–15% per year depending on clinical symptoms. The prophylactic implantation of a defibrillator is the only reliable therapy.

BrS type 1 (genetic) is caused by mutations in the SCN5A gene that codes for the sodium ion channel alpha subunit Nav1.5. Causative mutations in SCN5A (BrS1) can be detected in up to 25% of patients with BrS. More than 300 causative mutations are described that generally lead to a functional loss of a SCN5A allele.

In 5–10% of cases with BrS type 1 ECG other types of BrS are present. Some patients show causative mutations in the calcium ion channel genes CACNA1C (alpha-1C subunit, calcium channel, Cav1.2, BrS3) and CACNB2 (beta-2 subunit, BrS4). Besides ST-segment elevation these mutations result in relatively short QTc of 330–370 ms. A recently identified type is caused by mutations in the SCN10A gene and is probably responsible for some of the cases. Some types are very rare and are therefore not part of routine diagnostics. In approx. 70% of all cases no causative mutation can be detected. The combination of certain polymorphisms seems to be associated with an up to 20-fold higer risk for BrS as well.