title: Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect.
abstract: Phenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sinus node dysfunction (SND) is observed with SCN5A mutations. SCN5A-E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype-phenotype relationship in a large family carrying SCN5A-E1784K and SCN5A-H558R polymorphism.
  
  
  
  Clinical work-up, follow-up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A-E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A-H558R did not significantly alter the phenotype of SCN5A-E1784K carriers. Fourteen SCN5A-E1784K patients underwent implantable cardioverter-defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8±3 months of follow-up. One patient without ICD also developed VF after 6.7 years. These 5 cases carried both SCN5A-E1784K and SCN5A-H558R. Functional characterization was achieved by expressing SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium currents were recorded using whole-cell patch-clamp techniques. Co-expression of SCN5A-E1784K and SCN5A-WT reduced INa,P to 70.03% of WT, shifted steady-state inactivation by -11.03 mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A-E1784K was co-expressed with SCN5A-H558R.
  
  
  
  We demonstrate a strong genotype-phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A-E1784K mutation described so far. Phenotype of LQTS is present during all decades of life, whereas CCD develops with increasing age. Phenotypic overlap may explain the high event rate in carriers.
authors.affiliation: Rhythmology and Electrophysiology, Department of Cardiology and Angiology Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Veltmann
authors.affiliation: Molecular Genetic Department, Masonic Medical Research Laboratory, Utica, NY, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martinez
authors.affiliation: Klinik für Innere Medizin, Cardiology Klinikum Ludwigsburg, Ludwigsburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolpert
authors.affiliation: 1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany DZHK partner site Heidelberg/Mannheim, Mannheim, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.affiliation: 1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany DZHK partner site Heidelberg/Mannheim, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schimpf
authors.affiliation: Molecular Genetic Department, Masonic Medical Research Laboratory, Utica, NY, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Pfeiffer
authors.affiliation: Molecular Genetic Department, Masonic Medical Research Laboratory, Utica, NY, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cáceres
authors.affiliation: Molecular Genetic Department, Masonic Medical Research Laboratory, Utica, NY, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.affiliation: Lankenau Institute for Medical Research, Philadelphia, USA dianah@mmrl.edu cantzelevitch@gmail.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.affiliation: Molecular Genetic Department, Masonic Medical Research Laboratory, Utica, NY, USA dianah@mmrl.edu cantzelevitch@gmail.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D053840:Brugada Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D000075224:Cardiac Conduction System Disease / Q000150:complications / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D002648:Child; D017147:Defibrillators, Implantable; D019468:Disease Management; D005190:Family; D005260:Female; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D014693:Ventricular Fibrillation / Q000209:etiology / Q000628:therapy; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: Brugada syndrome; channelopathies; conduction defect; electrophysiology; genetics; long QT syndrome