title: A Brugada syndrome proband with compound heterozygote SCN5A mutations identified from a Chinese family in Singapore.
abstract: OBJECTIVE
  Brugada syndrome (BrS) is a rare heritable ventricular arrhythmia. Genetic defects in SCN5A, a gene that encodes the α-subunit of the sodium ion channel Nav1.5, are present in 15-30% of BrS cases. SCN5A remains by far, the highest yielding gene for BrS. We studied a young male who presented with syncope at age 11. This proband was screened for possible disease causing SCN5A mutations. The inheritance pattern was also examined amongst his first-degree family members.
  
  
  RESULTS
  The proband had a baseline electrocardiogram that showed Type 2 BrS changes, which escalated to a characteristic Type I BrS pattern during a treadmill test before polymorphic ventricular tachycardia onset at a cycle length of 250 ms. Mutational analysis across all 29 exons in SCN5A of the proband and first-degree relatives of the family revealed that the proband inherited a compound heterozygote mutation in SCN5A, specifically p.A226V and p.R1629X from each parent. To further elucidate the functional changes arising through these mutations, patch-clamp electrophysiology was performed in TSA201 cells expressing the mutated SCN5A channels. The p.A226V mutation significantly reduced peak sodium current (INa) to 24% of wild type (WT) whereas the p.R1629X mutation abolished the current. To mimic the functional state in our proband, functional expression of the compound variants A226V + R1629X resulted in overall peak INa of only 13% of WT (P < 0.01).
  
  
  CONCLUSIONS
  Our study is the first to report a SCN5A compound heterozygote in a Singaporean Chinese family. Only the proband carrying both mutations displayed the BrS phenotype, thus providing insights into the expression and penetrance of BrS in an Asian setting.
authors.affiliation: National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
authors.forename: Boon Yew
authors.initials: BY
authors.lastname: Tan
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore Saw Swee Hock School of Public Health, Tahir Foundation Building, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore.
authors.forename: Rita Yu Yin
authors.initials: RY
authors.lastname: Yong
authors.affiliation: Molecular Genetics Department, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martinez
authors.affiliation: Department of Physiology and Biophysics, Université de Sherbrooke, 2500, boul. de l'Université, Sherbrooke, QC, Canada J1K2R1.
authors.forename: Robert
authors.initials: R
authors.lastname: Dumaine
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore.
authors.forename: Ying Xia
authors.initials: YX
authors.lastname: Chew
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore Saw Swee Hock School of Public Health, Tahir Foundation Building, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore.
authors.forename: Pavandip Singh
authors.initials: PS
authors.lastname: Wasan
authors.affiliation: National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
authors.forename: Chi Keong
authors.initials: CK
authors.lastname: Ching
authors.affiliation: National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
authors.forename: Kah Leng
authors.initials: KL
authors.lastname: Ho
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore.
authors.forename: Linda Seo Hwee
authors.initials: LS
authors.lastname: Gan
authors.affiliation: Department of Physiology and Biophysics, Université de Sherbrooke, 2500, boul. de l'Université, Sherbrooke, QC, Canada J1K2R1.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Morin
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore.
authors.forename: Alicia Poh Leng
authors.initials: AP
authors.lastname: Chong
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore.
authors.forename: Shiao Hui
authors.initials: SH
authors.lastname: Yap
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore.
authors.forename: Jia Ling
authors.initials: JL
authors.lastname: Neo
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore Lee Kong Chian School of Medicine, Nanyang Technological University, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Eric Peng Huat
authors.initials: EP
authors.lastname: Yap
authors.affiliation: Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore.
authors.forename: Shabbir
authors.initials: S
authors.lastname: Moochhala
authors.affiliation: National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
authors.forename: Daniel Thuan Tee
authors.initials: DT
authors.lastname: Chong
authors.affiliation: SAF Medical Corps, 701 Transit Road, Singapore 778910, Singapore.
authors.forename: Weien
authors.initials: W
authors.lastname: Chow
authors.affiliation: The Heart Institute, National University Hospital Main Building, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Swee Chong
authors.initials: SC
authors.lastname: Seow
authors.affiliation: Molecular Genetics Department, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, 99 Zhang Zhi Dong Road, Wuhan 430060, China hudan0716@hotmail.com mahesh@dso.org.sg teo.wee.siong@nhcs.com.sg.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore Department of Biological Sciences and Department of Chemistry, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore hudan0716@hotmail.com mahesh@dso.org.sg teo.wee.siong@nhcs.com.sg.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Uttamchandani
authors.affiliation: National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore hudan0716@hotmail.com mahesh@dso.org.sg teo.wee.siong@nhcs.com.sg.
authors.forename: Wee Siong
authors.initials: WS
authors.lastname: Teo
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People; D053840:Brugada Syndrome / Q000235:genetics*; D002460:Cell Line; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012846:Singapore; D017180:Tachycardia, Ventricular / Q000235:genetics*; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: Brugada syndrome; Channelopathy; Compound heterozygote; Nav1.5; SCN5A