Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clin Show more
Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients. Show less
Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are responsible for up to 50% of familial cases with hypertrophic cardiomyopathy (HC). Compared to patients with mutations in other sarc Show more
Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are responsible for up to 50% of familial cases with hypertrophic cardiomyopathy (HC). Compared to patients with mutations in other sarcomeric genes, patients with MYBPC3 mutations would have a milder form of the disease, with a lower incidence of sudden cardiac death. Because most of the mutations have been found in only one family, it is currently difficult to establish a correlation between a particular mutation and the HC phenotype. The aim of our study was to contribute to understanding of the role of MYBPC3 mutations in HC. We analysed the MYBPC3 exons and intron flanking regions in 10 patients from 10 families with at least two HC cases. After direct sequencing of polymerase chain reaction (PCR) fragments, we found three new mutations in three families (V771M, V342D, and A627V). These changes affected evolutionary conserved amino acids and were not found in 100 healthy controls. The Ala 627>Val was found homozygous in a 47-year-old patient with a severe form of HC, while his mother and a nephew were heterozygous carriers and asymptomatic. This fact suggests a dosage effect for mutations at the MYPBC3 gene. Show less