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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Elijah R. Behr
  • Eleonora Savio-Galimberti
  • Julien Barc
  • Anders G. Holst
  • Evmorfia Petropoulou
  • Bram P. Prins
  • Javad Jabbari
  • Margherita Torchio
  • Myriam Berthet
  • Yuka Mizusawa
  • Tao Yang
  • Eline A. Nannenberg
  • Federica Dagradi
  • Peter Weeke
  • Rachel Bastiaenan
  • Michael J. Ackerman
  • Haunsø, Stig
  • Antoine Leenhardt
  • Stefan Kääb
  • Vincent Probst
  • Richard Redon
  • Sanjay Sharma
  • Arthur Wilde
  • Jacob Tfelt-Hansen
  • Peter Schwartz
  • Dan M. Roden
  • Connie R. Bezzina
  • Olesen, Morten Steen Salling
  • Dawood Darbar
  • Pascale Guicheney
  • Lia Crotti
  • UK10K Consortium
  • Yalda Jamshidi

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.

Original languageEnglish
JournalCardiovascular Research
Issue number3
Pages (from-to)520-529
Number of pages10
Publication statusPublished - 1 Jun 2015

    Research areas

  • Action Potentials, Adult, Aged, Brugada Syndrome, Case-Control Studies, Cell Line, Computational Biology, DNA Mutational Analysis, Databases, Genetic, Europe, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Heredity, Humans, Male, Middle Aged, NAV1.8 Voltage-Gated Sodium Channel, Odds Ratio, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Saudi Arabia, Transfection, United States

ID: 162751132