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Cardiovasc Res. 2015 Jun 1;106(3):520-9. doi: 10.1093/cvr/cvv042. Epub 2015 Feb 17.

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study.

Author information

1
Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK yjamshid@sgul.ac.uk ebehr@sgul.ac.uk.
2
Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
3
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, Netherlands.
4
Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Novo Nordisk A/S, Denmark.
5
Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK.
6
Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark LEO Pharma A/S, Denmark.
7
IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
8
Inserm, UMR S1166, Faculté de Médecine Pierre et Marie Curie, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France Institute of Cardiometabolism & Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.
9
Department of Clinical Genetics, Academic Medical Center, Amsterdam.
10
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA Division of Pediatric Cardiology, Department of Pediatrics & Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
11
Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Department of Medicine and Surgery, University of Copenhagen, Copenhagen, Denmark.
12
AP-HP, Hôpital Bichat, Service de Cardiologie et Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France.
13
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
14
Inserm, UMR 1087, l'institut du Thorax, Nantes, France CHU Nantes, l'institut du Thorax, Service de Cardiologie, Nantes, France.
15
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, Netherlands Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia.
16
Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
17
IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy Inserm, UMR 1087, l'institut du Thorax, Nantes, France Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Abstract

AIMS:

Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration.

METHODS AND RESULTS:

A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970).

CONCLUSION:

Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

KEYWORDS:

Brugada syndrome; Genetics; QRS duration; Rare variants; SCN10A

PMID:
25691538
PMCID:
PMC4447806
DOI:
10.1093/cvr/cvv042
[Indexed for MEDLINE]
Free PMC Article

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