Brugada Syndrome - Genetics and Pathophysiology

Genetics and Pathophysiology

Type OMIM Mutation Notes
B1 601144 SCN5A alpha subunit of the sodium channel. Current through this channel is commonly referred to as INa. Gain of this channel leads to an unopposed Ito current (KCND2)
B2 611778 GPD1L Glycerol-3-phosphate dehydrogenase like peptide
B3 114205 CACNA1C Alpha subunit of cardiac L-type calcium channel.
B4 600003 CACNB2 Beta-2 subunit of the voltage dependent L-type calcium channel.
B5 604433 KCNE3 which coassembles with KCND3 Beta subunit to KCND3. Modulates the Ito potassium outward current
B6 600235 SCN1B Beta-1 subunit of the sodium channel SCN5A

Approximately 20% of the cases of Brugada syndrome have been shown to be associated with mutation(s) in the gene that encodes for the sodium ion channel in the cell membranes of the muscle cells of the heart (the myocytes). The gene, named SCN5A, is located on the short arm of the third chromosome (3p21). Loss-of-function mutations in this gene lead to a loss of the action potential dome of some epicardial areas of the right ventricle. This results in transmural and epicardial dispersion of repolarization. The transmural dispersion underlies ST-segment elevation and the development of a vulnerable window across the ventricular wall, whereas the epicardial dispersion of repolarization facilitates the development of phase 2 reentry, which generates a phase 2 reentrant extrasystole that captures the vulnerable window to precipitate ventricular tachycardia and/or fibrillation that often results in sudden cardiac death. At present time however, all the reported patients who died because of the disease and were submitted to detailed autopsy study have shown a structural right ventricular pathology underlying the syndrome.

Over 160 mutations in the SCN5A gene have been discovered to date, each having varying mechanisms and effects on function, thereby explaining the varying degrees of penetration and expression of this disorder.

An example of one of the mechanisms in which a loss of function of the sodium channel occurs is a mutation in the gene that disrupts the sodium channel's ability to bind properly to ankyrin-G, an important protein mediating interaction between ion channels and cytoskeletal elements. Very recently a mutation in a second gene, Glycerol-3-phosphate dehydrogenase 1-like gene (GPD1L) has been shown to result in Brugada Syndrome in a large multigenerational family (London, 2006). This gene acts as an ion channel modulator in the heart, although the exact mechanism is not yet understood.

Recently Antzelevitch has identified mutations in the L-type calcium channel subunits (CACNA1C (A39V and G490R) and CACNB2 (S481L)) leading to ST elevation and a relatively short QT interval (below 360 msec). For a comprehensive list of all mutations see

This condition is inherited in an autosomal dominant pattern and is more common in males. In addition it has a higher prevalence in most Asian populations.

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