HYPERTROPHIC CARDIOMYOPATHY
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy
Sara L. Van Driest, BA*,
Vlad C. Vasile, MD*,
Steve R. Ommen, MD, FACC ,
Melissa L. Will, BS*,
A. Jamil Tajik, MD, FACC, ,
Bernard J. Gersh, MD, FACC and
Michael J. Ackerman, MD, PhD, FACC*,,,*
* Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota
Department of Internal Medicine, Division of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, Minnesota
Manuscript received April 23, 2004;
revised manuscript received June 25, 2004,
accepted July 28, 2004.
* Reprint requests and correspondence: Dr. Michael J. Ackerman, Sudden Death Genomics Laboratory, 501 Guggenheim, 200 First Street SW, Rochester, Minnesota 55905 (Email: ackerman.michael{at}mayo.edu).
OBJECTIVES: We sought to determine the frequency and phenotype of mutations in myosin binding protein C (MYBPC3) in a large outpatient cohort of patients with hypertrophic cardiomyopathy (HCM) seen at our tertiary referral center.
BACKGROUND: Mutations in MYBPC3 are one of the most frequent genetic causes of HCM and have been associated with variable onset of disease and prognosis. However, the frequency of mutations and associated clinical presentation have not been established in a large, unrelated cohort of patients.
METHODS: Using deoxyribonucleic acid from 389 unrelated patients with HCM, each protein coding exon of MYBPC3 was analyzed for mutations by polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. Clinical data were extracted from patient records blinded to patient genotype.
RESULTS: Of 389 patients with HCM, 71 (18%) had mutations in MYBPC3. In all, 46 mutations were identified, 33 of which were novel (72%). Patients with MYBPC3 mutations did not differ significantly from patients with thick filament-HCM, thin filament-HCM, or genotype-negative HCM with respect to age at diagnosis, degree of hypertrophy, incidence of myectomy, or family history of HCM or sudden death. Patients with multiple mutations (n = 10, 2.6%) had the most severe disease presentation.
CONCLUSIONS: This study defines the frequency and associated phenotype for MYBPC3 and/or multiple mutations in HCM in the largest cohort to date. In this cohort, unrelated patients with MYBPC3-HCM virtually mimicked the phenotype of those with mutations in the beta-myosin heavy chain. Patients with multiple mutations had the most severe phenotype.
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Abbreviations and Acronyms
| | DHPLC = denaturing high-performance liquid chromatography | | DNA = deoxyribonucleic acid | | HCM = hypertrophic cardiomyopathy | | ICD = implantable cardioverter-defibrillator | | LVOTO = left ventricular outflow tract obstruction | | LVWT = left ventricular wall thickness | | MYBPC3 = myosin binding protein C | | MYH7 = beta-myosin heavy chain | | SCD = sudden cardiac death |
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