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

• Published in: Circulation (New York, N.Y.) N.Y.), 2002-12, Vol.106 (24), p.3085-3090
• Main Authors: VAN DRIEST, Sara L, ACKERMAN, Michael J, OMMEN, Steve R, SHAKUR, Rameen, WILL, Melissa L, NISHIMURA, Rick A, TAJIK, A. Jamil, GERSH, Bernard J
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Cardiology. Vascular system; Cardiomyopathy, Hypertrophic - epidemiology; Cardiomyopathy, Hypertrophic - genetics; Child; Child, Preschool; Cohort Studies; Disease Progression; DNA Mutational Analysis; Female; Genotype; Heart; Humans; Infant; Infant, Newborn; Male; Medical sciences; Middle Aged; Minnesota - epidemiology; Mutation; Myocarditis. Cardiomyopathies; Myosin Heavy Chains - genetics; Predictive Value of Tests; Prevalence; Tropomyosin - genetics; Troponin T - genetics; Ventricular Myosins - genetics
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000042675.59901.14

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. 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. 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.