Abstract 1925: MYBPC3, MYH6, TPM1, TNNC1 and TNNI3 Mutations Identified in 313 Patients With Dilated Cardiomyopathy
The genetic basis of familial dilated cardiomyopathy (FDC) has been well established, and 30 genes are implicated in its causation. However, investigating the mutation frequencies of these genes in large cohorts of patients with dilated cardiomyopathy (DCM) is challenging. Locus heterogeneity (many genes) and allelic heterogeneity (mutations involving any coding nucleotide) greatly complicate investigational strategies, and Sanger-based sequencing, still the gold standard, is expensive. From our cohort of carefully phenotyped DCM probands, 183 with FDC and 130 with idiopathic dilated cardiomyopathy (IDC), we utilized the NHLBI’s Resequencing and Genotyping Service (RS&G) in 2006 to perform bidirectional sequencing of genomic DNAs from these subjects in the coding sequence and near intron/exon boundaries of 6 DCM genes (MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP). We found mutations that were likely or possibly disease-causing in 32 probands (10.2%). To extend these findings, we recently performed bidirectional sequencing of five additional genes in the same cohort, again with RS&G support. In 38 probands, we identified 33 unique missense and 2 splice site variants (12.1% overall) that were absent in 253 control subjects (506 chromosomes). These included 15 probands (4.8%) with 12 missense and 2 splice site myosin binding protein C (MYBPC3) mutations, 12 probands (3.8%) with 10 α-myosin heavy chain (MYH6) mutations, six probands (1.9%) with six tropomyosin 1 (TPM1) mutations, four probands (1.3%) with four troponin C (TNNC1) mutations, and two probands (0.6%) with the same cardiac troponin I (TNNI3) mutation. These 38 probands included 14 of 130 with IDC (10.8%) and 24 of 183 with FDC (13.1%). Sequencing of all available relatives is underway to assess segregration of mutations with disease. Some probands harbor multiple mutations.
Conclusions: Mutations of these five genes each account for a significant fraction of the genetic cause of FDC/IDC. The frequency of mutations in these five genes is similar for IDC and FDC. The resequencing data from 11 genes in both RS&G studies collectively accounts for 22.3% of DCM.