👤 Raija Miettinen

Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease caused by mutations in genes encoding sarcomeric proteins. To assess the genetic background and phenotypic expression of HCM in eastern Finland, we screened 35 unrelated patients with HCM from the Kuopio University Hospital area for variants in 9 genes encoding sarcomeric proteins with the PCR-SSCP method. We herewith describe our previous findings in five sarcomeric genes and also report hitherto unpublished data on four additional sarcomeric genes. Mutations in the cardiac myosin-binding protein C gene (MYBPC3) were most frequent, accounting for 26% of cases. A novel mutation (Gln1061X) in this gene was the most common mutation, found in 6 of 35 families and accounting for 17% of all cases. Other novel mutations in MYBPC3 (IVS5-2A --> C, IVS14-13G --> A, and Ex25deltaLys) were found in one family each. A previously described alpha-tropomyosin (TPM1) mutation (Asp175Asn) was found in 11% of cases. Haplotype analysis suggested that the two most common variants (MYBPC3-Gln1061X and TPM1-Asp175Asn) were founder mutations. Only one mutation (Arg719Trp) in the beta-myosin heavy chain gene (MYH7) was found in one family, and no disease-causing mutations were found in the genes encoding alpha-actin, cardiac troponin I, T, C, or myosin essential and regulatory light chains. Altogether, the aforementioned 6 mutations found in MYBPC3, TPM1, and MYH7 accounted for 61% of familial and 40% of all HCM cases. The mutations were associated mostly with benign or intermediary phenotypes with only few HCM-related deaths. We conclude that the genetic profile of HCM in eastern Finland is unique, characterized by few founder mutations with benign or intermediary phenotypes. Show less

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in genes encoding sarcomere proteins. This study screened all patients with HCM from the Kuopio University Hospital region in eastern Finland for variants in the cardiac myosin-binding protein C gene ( MYBPC3). All 35 exons of MYBPC3 were screened by the single-strand conformation polymorphism method in 37 unrelated patients with HCM. In MYBPC3 we identified seven novel (Gln1061X, IVS5-2A-->C, IVS14-13G-->A, Ex25DeltaLys, Pro147Leu, Ser236Gly, and Arg1138His) and two previously reported (Arg326Gln, Val896Met) variants, all of which are predicted to affect the structure of the encoded protein. Four of the nine variants, a nonsense mutation Gln1061X, a splice acceptor mutation (IVS5-2A-->C), a novel substitution in intron 14 (IVS14-13G-->A), and a novel 3-bp deletion in exon 25 (Ex25DeltaLys) were concluded to be disease-causing mutations because they cosegregated with the HCM phenotype or were absent in more than 200 normal chromosomes, or both. The mutation Gln1061X was found most frequently, being present in 6 families (23 subjects) while the other three mutations were found in single families each. Haplotype analysis indicated a likely founder effect among the families carrying the Gln1061X mutation. We found four novel mutations in MYBPC3, accounting for approx. 38% of familial and 24% of all cases of HCM. In our previous and unpublished studies no more frequent cause of HCM has been found in genetic analyses of other eight sarcomeric proteins. Consequently MYBPC3 is the predominant gene for HCM in eastern Finland. In addition, several amino acid substitutions in MYBPC3 suspected to be not associated with HCM were identified, indicating that some of the missense variants found in MYBPC3 are possibly not disease-causing mutations. Show less