Copy number variations of SCN5A in Brugada syndrome

Abstract

Background: Loss-of-function mutations in SCN5A are associated in ∼20% of Brugada syndrome (BrS) patients. Copy number variations (CNVs) have been shown to be associated with several inherited arrhythmia syndromes.

Objective: The purpose of this study was to investigate SCN5A CNVs among BrS probands.

Methods: The study cohort consisted of 151 BrS probands who were symptomatic or had a family history of BrS, sudden death, syncope, or arrhythmic diseases. We performed sequence analysis of SCN5A by the Sanger method. For detecting CNVs in SCN5A, we performed multiplex ligation-dependent probe amplification analysis of the 151 BrS probands.

Results: We identified pathogenic SCN5A mutations in 20 probands by the Sanger method. In 140 probands in whom multiplex ligation-dependent probe amplification was successfully performed, 4 probands were found to present different CNVs (deletion in 3 and duplication in 1). Three of them had fatal arrhythmia events; the remaining 1 was asymptomatic but had a family history. Mean age at diagnosis was 23 ± 14 years. All of the baseline 12-lead electrocardiograms showed PQ-interval prolongation. The characteristics of these 4 probands with CNVs were similar to those of the probands with mutations leading to premature truncation of the protein or missense mutations causing peak I_Na reduction >90%.

Conclusion: We identified SCN5A CNVs in 2.9% of BrS probands who were symptomatic or had a family history.

Keywords: Brugada syndrome; Copy number variation; Deletion; Duplication; Multiplex ligation-dependent probe amplification; SCN5A.