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CLINICAL RESEARCH

Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy

Sara L. Van Driest, BA^*, Michele A. Jaeger, BA^*, Steve R. Ommen, MD, FACC, Melissa L. Will, BS^*, Bernard J. Gersh, MD, FACC, A. Jamil Tajik, MD, FACC and Michael J. Ackerman, MD, PhD, FACC^*,*

^* Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Department of Internal Medicine/Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Manuscript received November 4, 2003; revised manuscript received March 18, 2004, accepted April 13, 2004.

^* Reprint requests and correspondence: Dr. Michael J. Ackerman, Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, Rochester, Minnesota 55905, USA.
ackerman.michael{at}mayo.edu

OBJECTIVES: We sought to determine the prevalence and phenotype of beta-myosin heavy chain gene MYH7 mutations in a large cohort of unrelated patients with hypertrophic cardiomyopathy (HCM).

BACKGROUND: Hypertrophic cardiomyopathy is a heterogeneous cardiac disease. MYH7 mutations are one of the most common genetic causes of HCM and have been associated with severe hypertrophy, young age of diagnosis, and high risk of sudden cardiac death. However, these clinical findings from large, family studies have not been confirmed in a large unrelated cohort.

METHODS: Deoxyribonucleic (DNA) samples obtained from 389 HCM outpatients seen at this tertiary referral center were analyzed for mutations, using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing for all 38 protein-coding exons of MYH7. Clinical data were extracted from patient records blinded to patient genotype.

RESULTS: Fifty-eight patients (15%) harbored 40 different mutations in MYH7. Compared with HCM patients without MYH7 mutations, HCM patients with MYH7 were younger at diagnosis (32.9 vs. 42.7 years, p = 0.0002), had more hypertrophy (left ventricular wall thickness of 24.2 vs. 21.1 mm, p = 0.0009), and more frequently underwent myectomy (60% vs. 38%, p = 0.002). The HCM patients with MYH7 mutations more often had a family history of HCM (43% vs. 29%, p = 0.006), but there was no difference in family history of sudden death (16% vs. 14%, p = NS).

CONCLUSIONS: In this setting, HCM patients with MYH7 were diagnosed at a younger age and had more hypertrophy, but they had no greater frequency of sudden death among first-degree relatives. Although these associations may prove useful for targeted gene screening, caution should be exercised in terms of using pathogenic status in risk stratification.

Abbreviations and Acronyms   DHPLC = denaturing high-performance liquid chromatography   HCM = hypertrophic cardiomyopathy   ICD = implantable cardioverter-defibrillator   LVWT = left ventricular wall thickness   MYH7 = beta-myosin heavy chain gene   PCR = polymerase chain reaction   SCD = sudden cardiac death   SNP = single-nucleotide polymorphism

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