CLINICAL AND PROGNOSTIC EVALUATION OF FAMILIAL HYPERTROPHIC CARDIOMYOPATHY IN 2 SOUTH-AFRICAN FAMILIES WITH DIFFERENT CARDIAC BETA-MYOSIN HEAVY-CHAIN GENE-MUTATIONS

Background-Familial hypertrophic cardiomyopathy is the most common inh erited cardiac disorder, with sudden cardiac death at a young age the most frequent cause of death in affected individuals. Some cases of fa milial hypertrophic cardiomyopathy are caused by missense mutations of the beta myosin heavy chain (beta MHC) gene on chromosome 14 and at l east 17 such mutations have been described. Recent reports suggest tha t a correlation exists between a specific beta MHC gene mutation and p rognosis in familial hypertrophic cardiomyopathy. This premise is curr ently being used as a basis to provide counselling for affected famili es. This mutation/prognosis association, however, has not been widely assessed as yet. The clinical and prognostic features of two South Afr ican families of mixed racial descent, in which different beta MHC gen e mutations were segregating, were studied to evaluate this correlatio n. The results were compared with those of previously published report s of European families carrying the same mutations. Methods-The beta M HC gene missense mutations in two affected families were identified by single strand conformation polymorphism analysis and sequencing (pedi gree 106: Arg403Trp; pedigree 108: Arg249Gln). All family members were , subjected to genotypic analysis using polymerase chain reaction ampl ification and restriction enzyme based mutation detection techniques. Clinical, electrocardiographic, and echocardiographic studies were per formed on genotypically affected individuals in these two kindreds. Re sults-The number of individuals identified in pedigree 106 with the Ar g403Trp mutation was 32. 10 individuals bore the Arg249Gln mutation in pedigree 108. The penetrance rate in adults (equal to or greater than 16 years), using the strict echocardiographic criterion of maximum le ft ventricular wall thickness greater than or equal to 13 mm, was 25% for pedigree 106 and 33% for pedigree 108. Familial hypertrophic cardi omyopathy compatible electrocardiographic and echocardiographic abnorm alities were seen in 60% of genotypically positive individuals aged gr eater than or equal to 16 years in pedigree 106 and 80% in pedigree 10 8. The prognosis was uniformly benign in the two families. For pedigre e 106 this corresponded to a report of no early sudden cardiac deaths in a French family with the Arg403Trp mutation. For pedigree 108 the a bsence of such deaths was in apparent contrast to the four cases repor ted in 24 genotypically affected individuals in a study of a kindred o f European ancestry bearing the Arg249Gln mutation. Conclusion-This st udy of a large South African kindred confirmed the benign nature of th e Arg403Trp mutation suggested in a previous report. The number and th e relatively young age of affected individuals in a second South Afric an family must be considered when comparing the absence of familial hy pertrophic cardiomyopathy associated deaths with the intermediate surv ival reported for the Arg249Gln mutation in a European family. This in vestigation lends support to current evidence relating specific beta M HC gene mutations to prognosis, which may be used as a basis to provid e counselling for affected families.