The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

• Published in: European journal of human genetics : EJHG 2009-10, Vol.17 (10), p.1241-1249
• Main Authors: Møller, Daniel Vega, Andersen, Paal Skytt, Hedley, Paula, Ersbøll, Mads Kristian, Bundgaard, Henning, Moolman-Smook, Johanna, Christiansen, Michael, Køber, Lars
• Format: Article
• Language: English
• Subjects: Adult; Amino Acid Sequence; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Capillary electrophoresis; Cardiology. Vascular system; Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cohort Studies; Compaction; Cytogenetics; Denmark; Dilated cardiomyopathy; DNA sequencing; Echocardiography - methods; Electrocardiography; Electrophoresis, Capillary - methods; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene polymorphism; General aspects. Genetic counseling; Genetic variance; Genetics of eukaryotes. Biological and molecular evolution; Heart; Human Genetics; Humans; Kinases; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Myocarditis. Cardiomyopathies; Pedigree; Phenotype; Phenotypic plasticity; Polymorphism, Single-Stranded Conformational; Rodents; Sarcomeres - genetics; Sarcomeres - metabolism; Sequence Analysis, DNA; Ventricle
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2009.34

We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7 , MYBPC3 , TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.