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

Sara L. Van Driest, Michael J. Ackerman, Steve R. Ommen, Rameen Shakur, Melissa L. Will, Rick A. Nishimura, A. Jamil Tajik, Bernard J. Gersh

Research output: Contribution to journalArticle

151 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3085-3090
Number of pages6
JournalCirculation
Volume106
Issue number24
DOIs
StatePublished - Dec 10 2002

Keywords

  • Cardiomyopathy
  • Death, sudden
  • Genetics
  • Hypertrophy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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