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

Abstract

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.

Recurrent and founder mutations in the Netherlands: mutation p.K217del in troponin T2, causing dilated cardiomyopathy*

“…4,6,7,9,12,14,[22][23][24][25] In these patients 17 TNNT2 mutations have been found, of which six (35%) were the specific TNNT2 p.K217del mutation. Two studies only analysed exon 13 of the TNNT2 gene.…”

“…These mutations have been found in familial DCM in about 7%, 7% and 3% of index patients, respectively. [4][5][6]9,[12][13][14][15][16][17] Screening for mutations in genes coding for sarcomeric proteins is therefore considered useful in cases of both familial and non-familial DCM, when other causes for DCM are excluded.…”

“…9 Mutations in these genes are found in up to 25% of cases. 4,10,11 Causative mutations in DCM are mostly found in the lamin A/C (LMNA), beta myosin heavy chain (MYH7), and troponin T (TNNT2) genes. These mutations have been found in familial DCM in about 7%, 7% and 3% of index patients, respectively.…”

Clinical utility gene card for: Dilated Cardiomyopathy (CMD)

“…The chance of carrying such an additional DCM-related mutation is believed to be o3%. 7,15,16 Index case in that family had not been tested: Idiopathic DCM is believed to be familial in about 30-50% of cases. Therefore, if an index patient has been clinically diagnosed with idiopathic DCM, and no genetic test has been performed, the chance for a first-degree relative to develop DCM may reach up to 15-25%.…”

“…11,12 Several studies have reported that DCM patients carrying more than one disease-associated mutation have an early onset, severe disease expression and a bad prognosis, which is most likely due to a gene-dosage effect. [13][14][15][16] It is expected that next-generation sequencing techniques will identify an increasing number of patients with such complex genotypes. Specificity:…”