Brugada syndrome: a genetic cause for sudden cardiac death

The role of antiarrhythmia therapy is yet to be determined.

A defect in the gene encoding for the cardiac L-type calcium channel appears to be responsible for a new clinical entity characterized by ST-segment elevation, short QT and sudden cardiac death.

Sudden cardiac death remains a major concern. Despite the marked decrease in death from heart disease, the incidence of sudden cardiac death has remained unchanged during the past three decades.

Reasons for sudden death

Sudden cardiac death in people aged younger than 35 is due to genetic causes. In this group of young individuals, the typical clinical picture is one of a lack of symptoms preceding sudden cardiac death. With the advent of molecular techniques, several genes responsible for sudden cardiac death have been identified and the phenotype modeled through expression of the gene in animal models.

Robert Roberts

Familial hypertrophic cardiomyopathy is the most common cause of sudden cardiac death in the young, followed by arrhythmias developed from genetic causes. Common forms have been the long QT syndrome and Brugada syndrome. Mutations in various ionic channels have been shown to cause most of these arrhythmias, including atrial fibrillation.

Antzelevitch et al described what they claim to be a new clinical entity responsible for sudden cardiac death. This discovery came from a genetic screening project in which 82 consecutive probands with a clinical diagnosis of Brugada syndrome underwent DNA sequencing of ion channel genes. Seven (8.5%) of these probands were found to have mutations in genes encoding the alpha 1 and beta 2 subunits of the cardiac L-type calcium channel.

In addition to ST-segment elevation and a family history of sudden cardiac death, three of the seven probands exhibited short QT intervals less than 360 milliseconds. Because these individuals had a short QT interval, experienced sudden cardiac death and had ST-segment elevation in B1 through B3, it is distinct from Brugada syndrome and thus claimed to be a new clinical entity.

One of the probands carried a heterozygous C1442T transition in exon 13 that led to a substitution of leucine for serine at position 481 of CACNB2 protein, which was not present in 400 ethnically matched control alleles. The mutation was located downstream of the beta subunit of the L-type calcium channel. The mutation was present in all six phenotype-positive and absent in all phenotype-negative family members.

The second proband showed heterozygous substitution of an alanine for a guanine at position 1468 in exon 10 of the CACNA1C gene that predicted substitution of arginine for a glycine at position 490 of the protein G490R. This was not present in 640 normal matched control alleles.

Proband three showed a heterozygous C116T transition in exon 2 of the CACNA1C gene that predicted a substitution of a valine for an alanine at position 39 of the protein A39V. This was not present in 404 ethnically-matched control alleles. The mutation in the calcium channel subunit was located in the N-terminus of the protein that contains the cytoplasmic link between domains I and II.

Gated voltage studies performed after expression in cultured cells show all three mutations associated with decreased voltage, indicating a loss of function in calcium channel activity.

Evidence supporting these mutations as the cause of clinical Brugada syndrome may be summarized as follows:

1. The S481L mutation segregated with the phenotype in a two-generation family.
2. None of the mutations were found in normal controls matched for ethnicity.
3. Expression of the mutant channels in Chinese hamster ovary cells showed a major loss of function consistent with Brugada syndrome phenotype and a shortened QT interval.
4. There is a clear genotype-phenotype correlation in the family with one of the mutations.

Co-segregation of the mutation with Brugada syndrome in the family and the in vitro expression provide adequate proof of the causative nature of the mutations. This syndrome adds yet another genetic cause for sudden cardiac death and, despite the prevalence and incidence of this genetic syndrome, is probably yet to be fully explored. Since this syndrome can be screened by surface electrocardiogram, the prevalence and incidence of this syndrome is likely to be determined in the near future. The role of antiarrhythmia therapy in the treatment of this disorder remains to be determined.

Robert Roberts, MD, is President and CEO of the University of Ottawa Heart Institute, and Section Editor of the Molecular Cardiology section of the Today in Cardiology Editorial Board.

For more information:

• Antzelevitch C, Pollevick GD, Coideiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115:442-449.