Coding Sequence Mutations Identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 Patients with Familial or Idiopathic Dilated Cardiomyopathy

Abstract

Background: More than 20 genes have been reported to cause idiopathic and familial dilated cardiomyopathy (IDC/FDC), but the frequency of genetic causation remains poorly understood. Methods and Results: Blood samples were collected and DNA prepared from 313 patients, 183 with FDC and 130 with IDC. Genomic DNA underwent bidirectional sequencing of six genes, and mutation carriers were followed up by evaluation of additional family members. We identified in 36 probands, 31 unique protein‐altering variants (11.5% overall) that were not identified 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 phentoype 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. These 32 probands included 14 of the 130 with IDC (10.8%) and 18 of the 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.

Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

“…He received medical therapy but later developed heart failure at age 14 and received a heart transplant at age 15. Two missense variants (TNNC1 Y5H and MYH7 R1045C) not seen in 246 controls and 253 controls, respectively, were detected in the proband (19,21). His mother, who was clinically unaffected (negative echocardiogram and electrocardiogram at age 47), was negative for both variants.…”

“…Samples from probands identified by the resequencing service as carriers of protein-altering variants, as well as any available samples from their relatives, were resequenced in our laboratory for confirmation and segregation analysis. Nucleotide changes were evaluated only if they were absent in all 246 control samples analyzed at the resequencing center (186 white, 23 Yoruban, 19 Asian, and 18 Hispanic) as reported previously (19,21).…”

“…Genomic DNA was extracted from whole blood and sequenced in both directions to detect nucleotide variants in TNNC1 (cTnC) as previously described (19,21). All exons and intron/exon boundaries were PCR-amplified by standard methods at SeattleSNPs.…”

Dilated Cardiomyopathy

“…In general, clinical and demographic factors, including family history, are not predictive of the results of genetic testing. 16 However, the likelihood of finding a mutation appears less likely in older patients (> 40 years) with non-familial disease. 23 Ordering providers should be aware of the limitations of genetic testing for DCM, especially as they apply to indeterminate and "negative" test results in index patients.…”

“…These studies suggest that mutations in sarcomeric genes, including TTN (titin), MYH7 (myosin heavy chain), TNNT2 (cardiac troponin T) and TPM1 (α-tropomyosin) are the most common etiologies, collectively accounting for ~30% of cases. 8,16,[21][22][23] Mutations in LMNA, which encodes Lamin A/C, a nuclear envelope protein, have been shown to cause different phenotypes associated with DCM, including DCM with limb-girdle or Emery-Dreifuss muscular dystrophy. Patients with LMNA mutations and DCM also have electrical instability (DCM+E), with supraventricular arrhythmias and atrioventricular block (AVB) often present before systolic dysfunction.…”