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

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Abstract

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

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Van Driest, S. L., Ackerman, M. J., Ommen, S. R., Shakur, R., Will, M. L., Nishimura, R. A., … Gersh, B. J. (2002). Prevalence and severity of “benign” mutations in the β-myosin heavy chain, cardiac troponin T, and α-tropomyosin genes in hypertrophic cardiomyopathy. Circulation, 106(24), 3085–3090. https://doi.org/10.1161/01.CIR.0000042675.59901.14

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