Some Brugada Syndrome Patients At Risk Of Sudden Cardiac Death Have GSTM3 Deletion

Pixabay License | Source: Petr Kuznetsov , No changes made.
Advertisement

Brugada syndrome (BrS) is a disorder of the heart rhythm that can result in sudden cardiac death, which may be triggered by circumstances, and has a genetic basis. Faster, abnormal rhythm may be triggered by electrolyte imbalances, certain drugs, fever, but also physiological transitions, such as day-night changes or after a meal. The triggers act upon an underlying BrS genetic background of susceptibility. The major known susceptibility gene is SCN5A, responsible for 20% of cases in Caucasians and 8% of cases in Han Chinese. The genetic basis is unknown in the remaining BrS patients. SCN5A encodes the cardiac sodium channel. Genetic copy number variations (CNVs) may be important in patients without SCN5A mutation, however this possibility has not been examined to date.

Charles Antzelevitch of Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, and colleagues from Taiwan, where the study patients were located, conducted a genome-wide CNV analysis in 301 BrS patients without SCN5A mutations using a multi-stage study design with an extreme phenotype sampling strategy. The findings were functionally tested in cell and zebrafish models of BrS. The results were published in EBioMedicine, a member of The Lancet journals.

Overall 90% of patients were male, a known risk factor, with an average age of diagnosis of 44 years. There was a family history in 21%, but no symptoms in 37% overall. Genomic analysis revealed 447 deletions and 55 amplifications of copy number, which deliberately excluded SCN5A. This copy number variation involved 91 gene deletions and 11 gene amplifications. GST mu family gene deletions were common. 

GSTM3 was deleted in 23% of the large validation cohort. The vast majority were heterozygous, that is they carried one functional GSTM3. In a small number of patients (34) with SCN5A mutation, none of them had GSTM3 deletion. Compared to BrS patients without GSTM3 or SCN5A mutations, sudden cardiac arrest and fainting (syncopy) was more common in GSTM3 mutated patients.

Advertisement

The authors confirmed that GSTM3 is expressed in the adult human right heart ventricle, but adult ventricular heart cells are not straightforward to convert into cell lines. Instead, the widely available human embryonic kidney HEK293 cell line was induced to stably express SCN5A to make it more representative of the heart. In order to mimic heterozygous GSTM3 deletion, small interfering RNA (siRNA) was used to reduce GSTM3 expression by half. In the presence of oxidative stress HEK293-SCN5A with GSTM3 interference appeared to hyperpolarize more than cells treated with control siRNA measured by patch clamp.

Zebrafish that were homo and heterozygous for GSTM3 deletion experience more heart arrhythmia than control fish when administered flecainide. Furthermore they experienced more ventricular tachycardia (VT) or ventricular fibrillation (VF) after controlled electrical stimulation.

The study population used in the reported study cannot be generalized to the whole BrS population as SCN5A mutated patients were specifically excluded, which is a limitation. Future prospective cohort studies could ascertain the relative risks of SCN5A and GSTM3 mutations.

β€œIn terms of clinical implications, our study identified a deletion of GSTM3 in BrS patients, which is associated with reduced INa, suggesting that the deletion could be a genetic modifier of the BrS phenotype. In addition, it could be used as a risk predictor in patients with BrS,” concluded the authors.

Source

  1. https://www.sciencedirect.com/science/article/pii/S2352396420302188