Familial Hypertophic Cardiomyopathy: many genes, how many diseases?

Many genetic conditions are considered a single disease. However, molecular analysis often revealed a wide genetic heterogeneity. Recently, new classifications based on the molecular defect, rather than clinical presentation, have been proposed. Familial Hypertrophic Cardiomyopathy (FHC) is transmitted as autosomal dominant trait with a prevalence of about 1/500. The disease is characterised by a hypertrophied and non-dilated left ventricle. The clinical course of the disease is heterogeneous: some patients remain asymptomatic, others die suddenly. Mutations causing disease in ten cardiac contractile proteins have been identified in FHC patients. Recently mutations on a non sarcomeric protein gene have also been identified as responsible of FHC. Genotype-phenotype correlation is crucial to the understanding of the natural history of FHC and possibly to separate heterogeneous clinical presentations into different diseases. Genetic definition of FHC may also have to be reconsidered including the clinical interpretation of possible recessive mutations, double heterozygous mutations, and mutations on two genes in the same subject. We believe that it is crucial to perform the molecular characterisation of patients on several loci. Due to the large number of genes responsible for this disease, we have started a pilot study to organise an Italian laboratory diagnostic network, and we look forward to join other European laboratories working in the same field. Our activity has focused on search of mutations in MYH7, MYBPC3, TPM1 and TNNT2 genes using the DHPLC technology and automated sequencing. A total of 26 different mutations have been identified. Specific cases will be reported in our presentation.