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Compound Heterozygous SCN5A Gene Mutations in Aasymptomatic Brugada Syndrome Child

Genomic Unit for the Diagnosis of Human Pathologies, Centre for Genomics, Bioinformatics and Biostatistics, San Raffaele Scientific Institute, Milano, Italy
Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, TX, USA
Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke’s Episcopal Hospital,Houston, TX, USA
Unit of Arrhythmology, Cardiotoracovascular Department, San Raffaele Scientific Institute, Milano, Italy
Krannert Institute of Cardiology, Indiana University, Indianapolis, IN, USA
Department of Arrhythmology, Maria Cecilia Hospital, Cotignola, Italy
Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele S.p.A., Milano, Italy
Vita-Salute San Raffaele University, Milano, Italy
Author to whom correspondence should be addressed.
Cardiogenetics 2012, 2(1), e11;
Submission received: 1 June 2012 / Revised: 30 July 2012 / Accepted: 3 August 2012 / Published: 17 September 2012


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 Brugada syndrome; arrhythmia; genetics; double mutant; sodium channel

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MDPI and ACS Style

Sommariva, E.; Vatta, M.; Xi, Y.; Sala, S.; Ai, T.; Cheng, J.; Pappone, C.; Ferrari, M.; Benedetti, S. Compound Heterozygous SCN5A Gene Mutations in Aasymptomatic Brugada Syndrome Child. Cardiogenetics 2012, 2, e11.

AMA Style

Sommariva E, Vatta M, Xi Y, Sala S, Ai T, Cheng J, Pappone C, Ferrari M, Benedetti S. Compound Heterozygous SCN5A Gene Mutations in Aasymptomatic Brugada Syndrome Child. Cardiogenetics. 2012; 2(1):e11.

Chicago/Turabian Style

Sommariva, Elena, Matteo Vatta, Yutao Xi, Simone Sala, Tomohiko Ai, Jie Cheng, Carlo Pappone, Maurizio Ferrari, and Sara Benedetti. 2012. "Compound Heterozygous SCN5A Gene Mutations in Aasymptomatic Brugada Syndrome Child" Cardiogenetics 2, no. 1: e11.

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