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. 2016 Sep 29;11(9):e0163514.
doi: 10.1371/journal.pone.0163514. eCollection 2016.

Large Genomic Imbalances in Brugada Syndrome

Irene Mademont-Soler  1 , Mel Lina Pinsach-Abuin  1 , Helena Riuró  1 , Jesus Mates  1 , Alexandra Pérez-Serra  1 , Mònica Coll  1 , José Manuel Porres  2 , Bernat Del Olmo  1 , Anna Iglesias  1 , Elisabet Selga  1 , Ferran Picó  1 , Sara Pagans  1   3 , Carles Ferrer-Costa  4 , Geòrgia Sarquella-Brugada  5 , Elena Arbelo  6 , Sergi Cesar  6 , Josep Brugada  5   6 , Óscar Campuzano  1   3 , Ramon Brugada  1   3   7
Affiliations

Large Genomic Imbalances in Brugada Syndrome

Irene Mademont-Soler et al. PLoS One. .

Abstract

Purpose: Brugada 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.

Methods: 220 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).

Results: The 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.

Conclusion: CNVs 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.

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Conflict of interest statement

Author RB received funding from FerrerInCode, a commercial company, for this study. Author CF-C received funding from Gendiag SL, a commercial company, for this study. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. SCN5A duplication in a Brugada syndrome patient.
Results of Multiplex ligation-dependent probe amplification (A) and Next-Generation Sequencing (B, patient in light blue) showing the duplication from exon 15 to 28 of SCN5A. Exon numbering according to isoform NM_198056.
Fig 2
Fig 2. Clinical data from the patient with the Copy Number Variant in SCN5A.
A. Basal electrocardiogram. B. Electrocardiogram after flecainide test, showing type I Brugada pattern. C. Family pedigree. The proband is indicated by an arrow. Subjects affected and unaffected by BrS are indicated by solid and open symbols, respectively. Genetic status for the SCN5A rearrangement is indicated by a superindex (+ or -).
See this image and copyright information in PMC

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