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Compound heterozygous SCN5A gene mutations in asymptomatic Brugada syndrome child

Elena Sommariva, Matteo Vatta, Yutao Xi, Simone Sala, Tomohiko Ai, Jie Cheng, Carlo Pappone, Maurizio Ferrari, Sara Benedetti
  • Elena Sommariva
    Genomic Unit for the Diagnosis of Human Pathologies, Centre for Genomics, Bioinformatics and Biostatistics, San Raffaele Scientific Institute, Milano, Italy
  • Matteo Vatta
    Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, TX, United States
  • Yutao Xi
    Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke’s Episcopal Hospital, Houston, TX, United States
  • Simone Sala
    Unit of Arrhythmology, Cardiotoracovascular Department, San Raffaele Scientific Institute, Milano, Italy
  • Tomohiko Ai
    Krannert Institute of Cardiology, Indiana University, Indianapolis, IN, United States
  • Jie Cheng
    Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke’s Episcopal Hospital, Houston, TX, United States
  • Carlo Pappone
    Department of Arrhythmology, Maria Cecilia Hospital, Cotignola, Italy
  • Maurizio Ferrari
    Genomic Unit for the Diagnosis of Human Pathologies, Centre for Genomics, Bioinformatics and Biostatistics, San Raffaele Scientific Institute, Milano; Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele S.p.A., Milano; Vita-Salute San Raffaele University, Milano, Italy
  • Sara Benedetti
    Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele S.p.A., Milano, Italy | benedetti.sara@hsr.it

Abstract

Loss-of-function mutations in the SCN5A gene, encoding the cardiac Nav1.5 sodium channel, have been previously associated with Brugada syndrome (BrS). Despite the low prevalence of the disease, we identified a patient carrying two SCN5A mutations. We aimed at establishing a correlation between genotype, clinical phenotype and in vitro sodium current. A 3-year-old boy presented with right bundle branch block and ST-segment elevation. Genetic analysis and electrophysiology studies in transfected HEK293 cells were performed to identify possibly disease-causing variants and assess their effect on sodium channel function. Two SCN5A variants were identified: a new frameshift deletion causing premature truncation of the putative protein (c.3258_3261del4) and a missense substitution (p.F1293S). In vitro studies revealed that the truncated mutant did not produce functional channels and decreased total sodium current when co-expressed with p.F1293S channels compared to p.F1293S alone. In addition, p.F1293S channels presented with a steep slope of steady-state activation voltagedependency, which was shifted towards more positive potentials by the co-expression with the truncated channel. p.F1293S channels also showed shift towards more positive potentials of the steady-state inactivation both alone and co-expressed with the deletion mutant. Our data identified a severe reduction of sodium channel current associated with two distinct SCN5A changes. However, all mutation carriers were asymptomatic and BrS electrocardiogram was observed only transiently in the compound heterozygous subject. These observations underline the difficulty of genotype/ phenotype correlations in BrS patients and support the idea of a polygenic disorder, where different mutations and variants can contribute to the clinical phenotype.

Keywords

Brugada syndrome, arrhythmia, genetics, double mutant, sodium channel.

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Submitted: 2012-06-01 16:44:04
Published: 2012-09-17 15:29:07
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Copyright (c) 2012 Elena Sommariva, Matteo Vatta, Yutao Xi, Simone Sala, Tomohiko Ai, Jie Cheng, Carlo Pappone, Maurizio Ferrari, Sara Benedetti

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