title: Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK yjamshid@sgul.ac.uk ebehr@sgul.ac.uk.
authors.forename: Elijah R
authors.initials: ER
authors.lastname: Behr
authors.affiliation: Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Savio-Galimberti
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.affiliation: 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.
authors.forename: Anders G
authors.initials: AG
authors.lastname: Holst
authors.affiliation: Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK.
authors.forename: Evmorfia
authors.initials: E
authors.lastname: Petropoulou
authors.affiliation: Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK.
authors.forename: Bram P
authors.initials: BP
authors.lastname: Prins
authors.affiliation: 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.
authors.forename: Javad
authors.initials: J
authors.lastname: Jabbari
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Torchio
authors.affiliation: 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.
authors.forename: Myriam
authors.initials: M
authors.lastname: Berthet
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mizusawa
authors.affiliation: Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam.
authors.forename: Eline A
authors.initials: EA
authors.lastname: Nannenberg
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Dagradi
authors.affiliation: Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Weeke
authors.affiliation: Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bastiaenan
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: 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.
authors.forename: Stig
authors.initials: S
authors.lastname: Haunso
authors.affiliation: AP-HP, Hôpital Bichat, Service de Cardiologie et Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Leenhardt
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.affiliation: Inserm, UMR 1087, l'institut du Thorax, Nantes, France CHU Nantes, l'institut du Thorax, Service de Cardiologie, Nantes, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.affiliation: Inserm, UMR 1087, l'institut du Thorax, Nantes, France CHU Nantes, l'institut du Thorax, Service de Cardiologie, Nantes, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.affiliation: Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sharma
authors.affiliation: 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.
authors.forename: Arthur
authors.initials: A
authors.lastname: Wilde
authors.affiliation: 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.
authors.forename: Jacob
authors.initials: J
authors.lastname: Tfelt-Hansen
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
authors.forename: Peter
authors.initials: P
authors.lastname: Schwartz
authors.affiliation: Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.affiliation: Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Olesen
authors.affiliation: Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
authors.affiliation: 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.
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.affiliation: 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.
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.affiliation: Human Genetics Research Centre, ICCS, St George's University of London, London SW17 0RE, UK yjamshid@sgul.ac.uk ebehr@sgul.ac.uk.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Jamshidi
mesh_terms: D000200:Action Potentials; D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D016022:Case-Control Studies; D002460:Cell Line; D019295:Computational Biology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D005060:Europe; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D008297:Male; D008875:Middle Aged; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012529:Saudi Arabia; D014162:Transfection; D014481:United States
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human
keywords: Brugada syndrome; Genetics; QRS duration; Rare variants; SCN10A