MALIGNANT FAMILIAL HYPERTROPHIC CARDIOMYOPATHY IN A FAMILY WITH A 453ARG-]CYS MUTATION IN THE BETA-MYOSIN HEAVY-CHAIN GENE - COEXISTENCE OFSUDDEN-DEATH AND END-STAGE HEART-FAILURE

Recent genotype-phenotype correlation studies in familial hypertrophic cardiomyopathy (FHC) have revealed that some mutations in the beta-my osin heavy chain (BMHC) gene may be associated with a high incidence o f sudden death and a poor prognosis, Coexistence of sudden death and e nd-stage heart failure in several families with FHC has recently being reported; however, the genetic basis of such families has not been cl early demonstrated. A three-generation Chinese familial hypertrophic c ardiomyopathy (FHC) family (family HL1) with two cases of end-stage he art failure and three cases of sudden death was analyzed. The average age of death in the affected members in this family was 34 years old. Genetic linkage analysis using polymorphisms in the alpha- and beta-my osin heavy chain genes revealed that FHC in this family is significant ly linked to the BMHC gene without recombinations. Single-strand confo rmation polymorphism analysis of exons 8, 9 and 13 to 23 in the BMHC g ene showed a polymorphic band on exon 14 that is in complete linkage w ith the disease status in this family, DNA sequencing analysis in the affected members revealed an 453Arg --> Cys mutation in the BMHC gene. To our knowledge this is the first reported mutation of FHC in Chines e. Our data suggest that the 453Arg --> Cys mutation is associated wit h a malignant clinical course in FHC due not only to sudden death but also to end-stage heart failure.