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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)

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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

Corresponding Author

Keywords Brugada Syndrome ; Qrs Duration ; Scn10a ; Genetics ; Rare Variants; Pr Interval; Arrhythmia Syndromes; Atrial-fibrillation; Heart-rate; Association; Conduction; Mutations; Duration; Channels; Sequence

ISSN (print) / ISBN 0008-6363

e-ISSN 1755-3245

Journal Cardiovascular Research

Quellenangaben Volume: 106, Issue: 3, Pages: 520-529

Publisher Oxford University Press

Publishing Place Oxford

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Human Genetics (IHG)