CLINICAL STUDY
Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin t genes in hypertrophic cardiomyopathy
A comprehensive outpatient perspective
Michael J. Ackerman, MD, PhD*  ,*,
Sara L. VanDriest, BA,
Steve R. Ommen, MD, FACC*,
Melissa L. Will, BS*,
Rick A. Nishimura, MD, FACC*,
A. Jamil Tajik, MD, FACC* and
Bernard J. Gersh, MB, ChB, DPhil, FACC*
* Department of Internal Medicine/Division of Cardiovascular DiseasesRochester, Minnesota, USA
Pediatric and Adolescent Medicine/Division of Pediatric CardiologyRochester, Minnesota, USA
Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
Manuscript received June 14, 2001;
revised manuscript received February 20, 2002,
accepted April 1, 2002.
* Reprint requests and correspondence: Dr. Michael J. Ackerman, Pediatric Cardiology E9, Mayo Clinic, 200 First Street, Rochester, Minnesota 55905 USA.
ackerman.michael{at}mayo.edu
OBJECTIVES: The goal of this study was to determine the prevalence of "malignant" mutations in hypertrophic cardiomyopathy (HCM).
BACKGROUND: Previous genotype-phenotype studies have implicated four mutations (R403Q, R453C, G716R and R719W) as highly malignant defects in the beta-myosin heavy chain (MYH7). In the cardiac troponin T gene (TNNT2), a specific mutation (R92W) has been associated with high risk of sudden death. Routine clinical screening for these malignant mutations has been suggested to identify high-risk individuals.
METHODS: We screened 293 unrelated individuals with HCM seen at the Mayo Clinic in Rochester, Minnesota, between April 1997 and October 2000. Deoxyribonucleic acid (DNA) was obtained after informed consent; amplification of MYH7 exons 13 (R403Q), 14 (R453C) and 19 (G716R and R719W), and TNNT2 exon 9 (R92W) was performed by polymerase chain reaction. The mutations were detected using denaturing high-performance liquid chromatography and automated DNA sequencing.
RESULTS: The mean age at diagnosis was 42 years with 53 patients diagnosed before age 25. The mean maximal left ventricular wall thickness was 21 mm. Nearly one-third of cases were familial and one-fourth had a family history of sudden cardiac death. Only 3 of the 293 patients possessed one of the five "malignant" mutations, and all 3 patients were <25 years of age at presentation (p < 0.006).
CONCLUSIONS: This finding underscores the profound genetic heterogeneity in HCM. Only 1% of unrelated individuals seen at a tertiary referral center for HCM possessed one of the five "malignant" mutations that were examined. Routine clinical testing for these specific mutations is of low yield.
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Abbreviations and Acronyms
| | DHPLC | | denaturing high-performance liquid chromatography | | DNA | | deoxyribonucleic acid | | HCM | | hypertrophic cardiomyopathy | | ICD | | implanted cardioverter defibrillator | | LVOTO | | left ventricular outflow tract obstruction | | LVWT | | left ventricular wall thickness | | MYH7 | | cardiac beta-myosin heavy chain | | PCR | | polymerase chain reaction | | SCD | | sudden cardiac death | | TNNT2 | | troponin T |
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