Title: Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death
Authors: Rossenbacker, Tom ×
Carroll, Sheila J
Liu, Huajun
Kuipéri, Cuno
de Ravel, Thomy
Devriendt, Koenraad
Carmeliet, Peter
Kass, Robert S
Heidbuchel, Hein #
Issue Date: Nov-2004
Series Title: Heart Rhythm vol:1 issue:5 pages:610-615
Abstract: OBJECTIVES: The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation. BACKGROUND: Brugada syndrome and isolated cardiac conduction defect have been linked to SCN5A mutations. METHODS: Eleven members of a western European family underwent electrophysiologic investigations and mutation analysis of the SCN5A gene. Wild-type and mutant SCN5A channels were expressed in HEK293 cells, and whole cell currents were studied using patch clamp procedures. RESULTS: A novel mutation, R376H, in the first pore segment of SCN5A variably causes Brugada syndrome and/or conduction disease in a single family. Biophysical analysis demonstrated a significant current reduction for the mutant, a pathophysiologic profile consistent with Brugada syndrome and isolated cardiac conduction defect. Among 11 family members, 9 were carriers of the mutation. The proband's initial presentation was a saddleback Brugada ECG, atrial flutter, and diffuse conduction disturbances. He had no inducible ventricular arrhythmias but experienced sudden cardiac death. His brother was affected by atrial flutter and had a clear conduction disorder, but he did not display baseline or evocable ECG signs of Brugada syndrome. He received an implantable cardioverter-defibrillator that delivered one appropriate shock after 1 year of follow-up. The phenotype in the family members was highly variable and ranged from noninducible and inducible asymptomatic carriers of the mutations to isolated conduction disease and to symptomatic Brugada syndrome. CONCLUSIONS: We describe the functional characterization of a novel SCN5A pore mutation, R376H, with variable clinical expression in the same family. Differentiating between electrophysiologic entities (Brugada syndrome-isolated cardiac conduction defect) is more challenging. Recognition of factors modifying the clinical presentation may be important for clinical decision making.
ISSN: 1547-5271
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Molecular and Vascular Biology
Clinical Genetics Section (-)
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
× corresponding author
# (joint) last author

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