Copy number variations of SCN5A in Brugada syndrome

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.