CLINICAL-FEATURES AND PROGNOSTIC IMPLICATIONS OF FAMILIAL HYPERTROPHIC CARDIOMYOPATHY RELATED TO THE CARDIAC MYOSIN-BINDING PROTEIN-C GENE

Background-Little information is available on phenotype-genotype corre lations in familial hypertrophic cardiomyopathy that are related to th e cardiac myosin binding protein C (MYBPC3) gene. The aim of this stud y was to perform this type of analysis. Methods and Results-We studied 76 genetically affected subjects from nine families with seven recent ly identified mutations (SASint20, SDSint7, SDSint23, branch point int 23, Glu542Gln, a deletion in exon 25, and a duplication/ deletion in e xon 33) in the MYBPC3 gene. Detailed clinical, EGG, and echocardiograp hic parameters were analyzed. An intergene analysis was performed by c omparing the MYBPC3 group to seven mutations in the beta-myosin heavy- chain gene (beta-MHC) group (n = 52). There was no significant phenoty pic difference among the different mutations in the MYBPC3 gene. Howev er, in the MYBPC3 group compared with the beta-MHC group, (1) prognosi s was significantly better (P < 0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41 +/- 19 versus 35 +/- 17 years, P < 0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low ( 41% versus 62%), maximal wall thicknesses lower (12 +/- 4 versus 16 +/ - 7 mm, P < 0.03), and abnormal T waves less frequent (9% versus 45%, P < 0.02). Conclusions-These results are consistent with specific clin ical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the bet a-MHC gene. These findings could be particularly important for the pur pose of clinical management and genetic counseling in familial hypertr ophic cardiomyopathy.