Large Genomic Imbalances in Brugada Syndrome

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

doi:10.1371/journal.pone.0163514

Large Genomic Imbalances in Brugada Syndrome

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

Authors

Irene Mademont-Soler¹, Mel Lina Pinsach-Abuin¹, Helena Riuró¹, Jesus Mates¹, Alexandra Pérez-Serra¹, Mònica Coll¹, José Manuel Porres², Bernat Del Olmo¹, Anna Iglesias¹, Elisabet Selga¹, Ferran Picó¹, Sara Pagans^{1

3}, Carles Ferrer-Costa⁴, Geòrgia Sarquella-Brugada⁵, Elena Arbelo⁶, Sergi Cesar⁶, Josep Brugada^{5

6}, Óscar Campuzano^{1

3}, Ramon Brugada^{1

3

7}

Affiliations

¹ Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
² Arrhythmia Unit, Hospital Universitario Donostia, San Sebastian, Spain.
³ Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain.
⁴ Gendiag SL, Barcelona, Spain.
⁵ Arrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
⁶ Arrhythmia Unit, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain.
⁷ Cardiovascular Genetics Unit, Hospital Josep Trueta, Girona, Spain.

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.

Grants and funding

This work has been partially supported by Obra social la Caixa; Ministerio de Economía y Competitividad / Instituto de Salud Carlos III (Spain) (PI14/01773); and Proyecto Investigación Básica Cardiología 2015 de los Socios Estratégicos de la Sociedad Española de Cardiologia (Spain). MP-A acknowledges a predoctoral fellowship from Generalitat de Catalunya (2014FI_B 00586); and ES acknowledges a Sara Borrell postdoctoral fellowship from Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Gendiag SL provided support in the form of salary for author CF-C, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section.