The Phenotype-Genotype Correlation in BrS Patients with Mutations in the SCN5A and KCNH2 Genes



Elena V. Zaklyazminskaya1, Siamak Saber1, Irena Pronicheva2, Anna Shestak1, Marina Yakovleva1, Amiran Revishvili2
1 Petrovsky Russian Research Centre of Surgery, Russia
2 Vishnevsky Institute of Surgery, Russia

Introduction and Methods: The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST-segment elevation in V1-V3 leads and negative T wave on standard ECG. Hundred mutations are known in the genes encoding cardiac ion channels but the phenotype-genotype correlation is not completely understood.

We had under the observation 81BrS probands (M:F=7:1) and 144 relatives.

The coding sequences of the SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, MOG1, and KCNH2 genes were screened by Sanger sequencing. Cascade familial screening was performed for all available relatives in genotype-positive families.

Mutation Screening Results: Sixteen mutations in 16 male probands (20%) were found in the SCN5A gene. Six of 16 mutations lead to the premature truncating stop codon. Two missense-mutations (p.R25W and p.R397C) were found in KCNH2 gene in 2 probands (2.5%). None mutation was detected in the SCN1B, SCN2B, SCN3B, SCN4B, and MOG1 genes.

Phenotype-Genotype Correlation:
The most common complain were sudden death in the family (46%), non-triggered syncope (41%), ventricular arrhythmias (36%), and dizziness (17%). The surgical treatment was recommended to the 66 BrS probands (81%). The follow-up period was 30 months. Fifty-nine of them have got the ICDs, 15 had the appropriate shocks during follow-up period, 1 had died due to VT after device discharging. Seven probands had refused the ICD implantation and 4 of them died during the follow-up period. Prolongation of PR interval > 190 ms is more typical for patients with mutations in the SCN5A gene. The relative QTc shortening is more characteristic for BrS patients caused by mutations in KCNH2 gene.

Conclusions: The prevalence of the SCN5A-mediated forms of BrS in is 20%, and the routing genetic screening of SCN5A gene is reasonable in our population. The duration of PR and QTc shows gene-specific pattern.