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Timothy M. Olson, MD; Virginia V. Michels, MD; Jeffrey D. Ballew, MS; Sandra P. Reyna, MD; Margaret L. Karst, BA; Kathleen J. Herron, BA; Steven C. Horton, MD; Richard J. Rodeheffer, MD; Jeffrey L. Anderson, MD

JAMA. 2005;293:447-454.

Context  Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established.

Objectives  To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene.

Design, Setting, and Participants  Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement.

Main Outcome Measure  Correlation of identified mutations with cardiac phenotype.

Results  Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years).

Conclusions  Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.

Author Affiliations: Division of Cardiovascular Diseases, Department of Internal Medicine (Drs Olson and Rodeheffer, Mr Ballew, and Mss Karst and Herron), Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (Dr Olson), and Department of Medical Genetics (Dr Michels), Mayo Clinic College of Medicine, Rochester, Minn; and Cardiovascular Department (Drs Reyna, Horton, and Anderson), LDS Hospital, University of Utah, Salt Lake City.

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