Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.

Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, Tajik AJ, Gersh BJ
Circulation. 2002 106 (24): 3085-90

PMID: 12473556 · DOI:10.1161/01.cir.0000042675.59901.14

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 beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of alpha-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.

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.

MeSH Terms (25)

Adolescent Adult Aged Aged, 80 and over Cardiomyopathy, Hypertrophic Child Child, Preschool Cohort Studies Disease Progression DNA Mutational Analysis Female Genotype Humans Infant Infant, Newborn Male Middle Aged Minnesota Mutation Myosin Heavy Chains Predictive Value of Tests Prevalence Tropomyosin Troponin T Ventricular Myosins

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