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Behr, E.R.* ; Savio-Galimberti, E.* ; Barc, J.* ; Holst, A.G.* ; Petropoulou, E.* ; Prins, B.P.* ; Jabbari, J.* ; Torchio, M.* ; Berthet, M.* ; Mizusawa, Y.* ; Yang, T.* ; Nannenberg, E.A.* ; Dagradi, F.* ; Weeke, P.* ; Bastiaenan, R.* ; Ackerman, M.J.* ; Haunso, S.* ; Leenhardt, A.* ; Kääb, S. ; Probst, V.* ; Redon, R.* ; Sharma, S.* ; Wilde, A.A.* ; Tfelt-Hansen, J.* ; Schwartz, P.* ; Roden, D.M.* ; Bezzina, C.R.* ; Olesen, M.S.* ; Darbar, D.* ; Guicheney, P.* ; Crotti, L. ; Jamshidi, Y.*

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

Cardiovasc. Res. 106, 520-529 (2015)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
BACKGROUND: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. OBJECTIVES: We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced 7 candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBΧ3 and ΤΒΧ5) 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 4/7 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=8.07x10-19). 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 to 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Brugada Syndrome ; Qrs Duration ; Scn10a ; Genetics ; Rare Variants; Pr Interval; Arrhythmia Syndromes; Atrial-fibrillation; Heart-rate; Association; Conduction; Mutations; Duration; Channels; Sequence
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 0008-6363
e-ISSN 1755-3245
Journal Cardiovascular Research
Quellenangaben Volume: 106, Issue: 3, Pages: 520-529 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
PubMed ID 25691538
DOI 10.1093/cvr/cvv042
WOS ID WOS:000359088400019
Scopus ID 84930331925
Erfassungsdatum 2015-02-20
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