Abstract 370: MHY7, TNNT2, SCN5A, CSRP3, LBD3, And TCAP Mutations Identified In 313 Patients With Dilated Cardiomyopathy
Mutations in numerous genes reported in association with familial dilated cardiomyopathy (FDC) suggest that it is largely a genetic disease. While genetic causation has been reported occasionally in idiopathic dilated cardiomyopathy (IDC), determining the mutation frequencies of genes in patients with IDC or FDC is challenging. Gathering large cohorts of carefully phenotyped FDC/IDC probands and their family members is time and effort intensive. Locus heterogeneity (many genes) and allelic heterogeneity (mutations can involve any coding nucleotides) greatly complicate investigational strategies. Further, sequencing, the gold standard, is expensive. We undertook a study of mutational data from 313 patients, 183 with FDC and 130 with IDC in our research repository, utilizing the resequencing service provided by the NHLBI. Genomic DNA underwent bidirectional sequencing of six genes, and mutations were evaluated in other family members as possible. In 36 probands, we identified 31 unique protein-altering variants (11.5% overall) absent in 253 control subjects (506 chromosomes). These included 13 probands (4.2%) with 12 β-myosin heavy chain (MYH7) mutations, nine probands (2.9%) with six different cardiac troponin T (TNNT2) mutations, eight probands (2.6%) carrying seven different cardiac sodium channel (SCN5A) mutations, three probands (1.0%) with three titin-cap or telethonin (TCAP) mutations, three probands (1.0%) with two LIM domain binding 3 (LDB3) mutations, and one proband (0.3%) with a muscle LIM protein (CSRP3) mutation. Four nucleotide changes did not segregate with phenotype and/or did not alter a conserved amino acid and were therefore considered unlikely to be disease-causing. Mutations in 11 probands were assessed as likely disease-causing, and in 21 probands were considered possibly disease-causing. Unexpectedly, these 32 probands included 14 of the 130 with IDC (10.8%) and 18 of 183 with FDC (9.8%).
Conclusions: Mutations of these six genes each account for a small fraction of the genetic cause of FDC/IDC. The frequency of possible or likely disease-causing mutations in these genes is similar for IDC and FDC.