on November 18, 2002
Published online before print November 18, 2002, doi: 10.1161/01.CIR.0000042675.59901.14
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Submitted on August 21, 2002
From the Department of Molecular Pharmacology and Experimental Therapeutics (S.L.V., M.J.A., M.L.W.), Department of Internal Medicine/Division of Cardiovascular Diseases (M.J.A., S.R.O., R.A.N., A.J.T., B.J.G.), and Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology (M.J.A., A.J.T.), Mayo Clinic, Rochester, Minn. R.S. was a 2001 Churchill Fellow in Cardiology from the University of Cambridge. * To whom correspondence should be addressed. E-mail: ackerman.michael{at}mayo.edu.
Background—Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of Methods and Results—A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant. Conclusions—These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course.
Revised on September 25, 2002
Accepted on September 26, 2002
Prevalence and Severity of "Benign" Mutations in the
Sara L. Van Driest BA, 
-Myosin Heavy Chain, Cardiac Troponin T, and 
-Tropomyosin Genes in Hypertrophic Cardiomyopathy
-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of 
-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown.
Key words: hypertrophy • cardiomyopathy • genetics • death, sudden
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