Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy is a genetically heterogeneous autosom al dominant disease, caused by mutations in several sarcomeric protein gene s. So far, seven genes have been shown to be associated with the disease wi th the beta-myosin heavy chain (MYH7) and the cardiac myosin binding protei n C (MYBPC3) genes being the most frequently involved. We performed electro cardiography (ECG) and echocardiography in 15 subjects with hypertrophic ca rdiomyopathy from a French Caribbean family. Genetic analyses were performe d on genomic DNA by haplotype analysis with microsatellite markers at each locus involved and mutation screening by single strand conformation polymor phism analysis. Based on ECG and echocardiography, eight subjects were affe cted and presented a classical phenotype of hypertrophic cardiomyopathy. Tw o new mutations cosegregating with the disease were found, one located in t he MYH7 gene exon 15 (Glu483Lys) and the other in the MYBPC3 gene exon 30 ( Glu1096 termination codon). Four affected subjects carried the MYH7 gene mu tation, two the MYBPC3 gene mutation, and two were doubly heterozygous for the two mutations. The doubly heterozygous patients exhibited marked left v entricular hypertrophy, which was significantly greater than in the other a ffected subjects. We report for the first time the simultaneous presence of two pathological mutations in two different genes in the context of familial hypertrophic ca rdiomyopathy. This double heterozygosity is not lethal but is associated wi th a more severe phenotype.