Sudden cardiac death in hypertrophic cardiomyopathy Variability in phenotypic expression of /?-myosin heavy chain mutations

Background: Recent identification of mutations in the $-myosin heavy chain gene (MYH7), a major responsible gene for HCM, lias provided the opportunity to characterize genotype-phenotype correlation in HCM families. In this study we analysed the phenotypic expression of two $-myosin heavy chain ($MHC) mutations in three unrelated HCM families. Methods: Living individuals from three unrelated HCM families (Families 1, 2, and 3) were screened by history, physical examination, electrocardiography, and two-dimensional echocardiography. Blood was collected from all individuals for DNA extraction. Polymerase chain reaction (PCR), restriction endonuclease digestion and chemical cleavage were utilized for detection of mutations. All mutations were confirmed by sequence analysis. Results: Identification of mutations: A missense mutation in exon 13 of the fiMHC gene (Arg403Gln) was detected in HCM patients from Families 1 and 2. PCR amplification of the exon 13 DNA, followed by Ddel digestion of the PCR product and gel electrophoresis, showed two fragments of 84 and 70 bp in normal individuals and four fragments of 84, 70, 52 and 32 bp in HCM patients. Sequence analysis showed substitution of an adenine for guanine at coding position 1208. In Family 3, a missense mutation in exon 16 of the $MHC gene (Vaf^Met) was detected in HCM patients. Chemical cleavage of the PCR products showed an uncleaved product of 337 bp in the normal individuals, while in the affected individuals, in addition to the uncleaved product, a 90 bp cleaved product was also detected, indicating th