Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin t genes in hypertrophic cardiomyopathy A comprehensive outpatient perspective

AbstractObjectivesThe goal of this study was to determine the prevalence of “malignant” mutations in hypertrophic cardiomyopathy (HCM).BackgroundPrevious 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.MethodsWe 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 MYH7exons 13 (R403Q), 14 (R453C) and 19 (G716R and R719W), and TNNT2exon 9 (R92W) was performed by polymerase chain reaction. The mutations were detected using denaturing high-performance liquid chromatography and automated DNA sequencing.ResultsThe 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).ConclusionsThis 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