FAMILIAL HYPERTROPHIC CARDIOMYOPATHY - MICROSATELLITE HAPLOTYPING ANDIDENTIFICATION OF A HOT-SPOT FOR MUTATIONS IN THE BETA-MYOSIN HEAVY-CHAIN GENE

Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetic ally heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, rec ently mapped to chromosome 14q11-12. Significant linkage was found wit h MYO I and MYO II in pedigree 720, but results were not conclusive fo r pedigree 730. Haplotype analysis of the six markers allowed identifi cation of affected individuals and of some unaffected subjects carryin g the disease gene. Two novel missense mutations were identified in ex on 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403 Arg-->Leu mutation was associated w ith incomplete penetrance, a high incidence of sudden deaths and sever e cardiac events, whereas the consequences of the 403 Arg-->Trp mutati on appeared less severe. Haplotyping of polymorphic markers in close l inkage to the beta-myosin heavy chain gene can, thus, provide rapid an alysis of non informative pedigrees and rapid detection of carrier sta tus. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.