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Abstract
PurposeBrugada syndrome (BrS) is a form of cardiac arrhythmia which may lead to sudden cardiac death. The recommended genetic testing (direct sequencing of SCN5A) uncovers disease-causing SNVs and/or indels in ~20% of cases. Limited information exists about the frequency of copy number variants (CNVs) in SCN5A in BrS patients, and the role of CNVs in BrS-minor genes is a completely unexplored field.Methods220 BrS patients with negative genetic results were studied to detect CNVs in SCN5A. 63 cases were also screened for CNVs in BrS-minor genes. Studies were performed by Multiplex ligation-dependent probe amplification or Next-Generation Sequencing (NGS).ResultsThe detection rate for CNVs in SCN5A was 0.45% (1/220). The detected imbalance consisted of a duplication from exon 15 to exon 28, and could potentially explain the BrS phenotype. No CNVs were found in BrS-minor genes.ConclusionCNVs in current BrS-related genes are uncommon among BrS patients. However, as these rearrangements may underlie a portion of cases and they undergo unnoticed by traditional sequencing, an appealing alternative to conventional studies in these patients could be targeted NGS, including in a single experiment the study of SNVs, indels and CNVs in all the known BrS-related genes.
Highlights
Brugada syndrome (BrS) is a form of cardiac arrhythmia, characterized by a typical electrocardiographic pattern of ST segment elevation in leads V1 to V3, and incomplete or complete right bundle branch block [1]
copy number variants (CNVs) in current BrS-related genes are uncommon among BrS patients
An additional 15% of patients can be molecularly diagnosed if the minor genes described as causing BrS are included in the genetic analysis (ABCC9, CACNA1C, CACNA2D1, CACNB2, FGF12, GPD1L, HCN4, KCND3, KCNE1L, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN10A, SLMAP and TRPM4) [3,6,7]
Summary
Brugada syndrome (BrS) is a form of cardiac arrhythmia, characterized by a typical electrocardiographic pattern of ST segment elevation in leads V1 to V3, and incomplete or complete right bundle branch block [1]. A common presentation of BrS is syncope, which is caused by fast polymorphic ventricular tachycardia. Such syncope typically occurs in the third and fourth decade of life, and usually at rest or during sleep. Screening for pathogenic variants in this gene uncovers mutations in approximately 20% of BrS patients [4,5]. An additional 15% of patients can be molecularly diagnosed if the minor genes described as causing BrS are included in the genetic analysis (ABCC9, CACNA1C, CACNA2D1, CACNB2, FGF12, GPD1L, HCN4, KCND3, KCNE1L, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN10A, SLMAP and TRPM4) [3,6,7]. A causal genetic variant is not found in a high percentage of patients with BrS
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