title: Disease-targeted sequencing of ion channel genes identifies de novo mutations in patients with non-familial Brugada syndrome.
abstract: Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20-25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants.
authors.affiliation: 1] Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan [2] Graduate Institute of Physiology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Jyh-Ming Jimmy
authors.initials: JM
authors.lastname: Juang
authors.affiliation: Department of Public Health, Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Tzu-Pin
authors.initials: TP
authors.lastname: Lu
authors.affiliation: Graduate Institute of Physiology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Liang-Chuan
authors.initials: LC
authors.lastname: Lai
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Chia-Chuan
authors.initials: CC
authors.lastname: Ho
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Yen-Bin
authors.initials: YB
authors.lastname: Liu
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Chia-Ti
authors.initials: CT
authors.lastname: Tsai
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Lian-Yu
authors.initials: LY
authors.lastname: Lin
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Wen-Jone
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Fu-Tien
authors.initials: FT
authors.lastname: Chiang
authors.affiliation: Department of Environmental and Occupational Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Shih-Fan Sherri
authors.initials: SF
authors.lastname: Yeh
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chuang
authors.affiliation: Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, National Taiwan University Hospital Taipei, 10002, Taiwan.
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
mesh_terms: D053840:Brugada Syndrome / Q000209:etiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000473:pathology; D053503:Epithelial Sodium Channels / Q000235:genetics*; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D000081033:Potassium Channels, Sodium-Activated; D051669:Shab Potassium Channels / Q000235:genetics*; D000097062:Kir5.1 Channel
chemical_list: D053503:Epithelial Sodium Channels; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000081033:Potassium Channels, Sodium-Activated; D051669:Shab Potassium Channels; C496992:KCNB2 protein, human; C576242:KCNJ16 protein, human; D000097062:Kir5.1 Channel; C585122:KCNT1 protein, human; C568320:SCN5A protein, human; C507045:SCNN1A protein, human