Published online before print October 4, 2004, doi: 10.1161/01.CIR.0000144458.58660.BB
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(Circulation. 2004;110:2163-2167.)
© 2004 American Heart Association, Inc.
Heart Failure |
SCN5A Mutation Associated With Dilated Cardiomyopathy, Conduction Disorder, and Arrhythmia
From the University of Colorado Cardiovascular Institute (W.P.M., L.K., M.R.G.T., P.R.F., D.D., E.W., L.M.), Human Medical Genetics Program (W.P.M., M.R.G.T., P.R.F., L.M.), and Division of Cardiology (E.W., L.M.), University of Colorado Health Sciences Center, Denver, Colo.
Reprint requests to Dr Luisa Mestroni, University of Colorado Cardiovascular Institute, Bioscience Park Center, 12635 E Montview Blvd, Suite 150, Aurora, CO 80010-7116. E-mail Luisa.Mestroni{at}UCHSC.edu
Received February 20, 2003; revision received May 4, 2004; accepted May 18, 2004.
Background— We studied a large family affected by an autosomal dominant cardiac conduction disorder associated with sinus node dysfunction, arrhythmia, and right and occasionally left ventricular dilatation and dysfunction. Previous linkage analysis mapped the disease phenotype to a 30-cM region on chromosome 3p22-p25 (CMD1E). This region also contains a locus for right ventricular cardiomyopathy (ARVD5) and the cardiac sodium channel gene (SCN5A), mutations that cause isolated progressive cardiac conduction defect (Lenègre syndrome), long-QT syndrome (LQT3), and Brugada syndrome.
Methods and Results— Family members were studied, and the positional candidate gene SCN5A was screened for mutations. We identified, by direct sequencing, a heterozygous G-to-A mutation at position 3823 that changed an aspartic acid to asparagine (D1275N) in a highly conserved residue of exon 21. This mutation was present in all affected family members, was absent in 300 control chromosomes, and predicted a change of charge within the S3 segment of domain III.
Conclusions— Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction and support the hypothesis that genes encoding ion channels can be implicated in dilated cardiomyopathies.
Key Words: genetics • cardiomyopathy • conduction • arrhythmia • heart block
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