Sudden cardiac death in hypertrophic cardiomyopathy

Background: Recent identification of mutations in the ß-myosinheavy chain gene (MYH7), a major responsible gene for HCM, hasprovided the opportunity to characterize genotype-phenotypecorrelation in HCM families. In this study we analysed the phenotypicexpression of two ß-myosin heavy chain (ßMHC)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. Bloodwas collected from all individuals for DNA extraction. Polymerasechain reaction (PCR), restriction endonuclease digestion andchemical cleavage were utilized for detection of mutations.All mutations were confirmed by sequence analysis. Results:Identification of mutations: A missense mutation in exon 13of the ßMHC gene (Arg⁴⁰³Gln) was detected in HCM patientsfrom 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 andfour fragments of 84, 70, 52 and 32 bp in HCM patients. Sequenceanalysis showed substitution of an adenine for guanine at codingposition 1208. In Family 3, a missense mutation in exon 16 ofthe ßMHC gene (Val⁶⁰⁶Met) was detected in HCM patients.Chemical cleavage of the PCR products showed an uncleaved productof 337 bp in the normal individuals, while in the affected individuals,in addition to the uncleaved product, a 90 bp cleaved productwas also detected, indicating the presence of a mismatch inone allele. Sequence analysis showed substitution of an adeninefor guanine in coding position 1817. Clinical Characteristics: Seven members of Family 1 had HCM,of whom five are alive. One patient died from sudden cardiacdeath (SCD) and another from recurrent cerebral embolL In Family2, 15 individuals had HCM of whom nine have died, seven fromSCD. The mean age at the time of SCD was 33 years. The thirdfamily is comprised of 11 affected individuals and one obligatecarrier, of whom one patient died at age 17 from progressiveheart failure. Two additional individuals in this family havealso succumbed to SCD to age 60. A variety of clinical and echocardiographicmanifestations of HCM were present in each family. Logrank test of Kaplan-Meier survival curves indicates thatArg⁴⁰³Gln mutation was associated with a poor prognosis in HCMfamilies as compared to Val⁶⁰⁶Met (P=0.034). Conclusions: ßMHC mutations despite showing variableclinical and echocardiographic manifestations of HCM are predictorsof survival in HCM families.