Coding Sequence Rare Variants Identified in MYBPC3 , MYH6 , TPM1 , TNNC1 , and TNNI3 From 312 Patients With Familial or Idiopathic Dilated Cardiomyopathy

Abstract

Background-Rare variants in Ͼ30 genes have been shown to cause idiopathic or familial dilated cardiomyopathy (DCM), but the frequency of genetic causation remains poorly understood. We have previously resequenced 9 genes in a cohort of idiopathic or familial DCM probands for rare variants, and now we report resequencing results for 5 more genes with established relationships to DCM. Methods and Results-Blood samples were collected, and DNA specimens were prepared from 312 patients, 181 with familial DCM and 131 with idiopathic DCM. Genomic DNA underwent bidirectional sequencing, and DNA of additional family members underwent analysis when a rare variant was identified. We identified rare variants in 34 probands (10.9% overall), including 29 unique protein-altering rare variants and 2 splicing variants that were absent in 246 control subjects (492 chromosomes). These variants were 12 MYBPC3 (myosin-binding protein C) in 13 (4.2%) probands, 8 MYH6 (␣-myosin heavy chain) in 10 (3.2%), 6 TPM1 (tropomyosin) in 6 (1.9%), 4 TNNC1 (cardiac troponin C) in 4 (1.3%), and 1 TNNI3 (cardiac troponin I) in 2 (0.6%). Variants were classified as likely or possibly disease causing in 13 and 20 probands, respectively (nϭ33; 10.6% overall). One MYH6 variant was classified as unlikely to be disease causing. Conclusion-Rare variants in these 5 genes likely or possibly caused 10.6% of DCM in this cohort. When combined with our prior resequencing reports, Ϸ27% of DCM probands had possible or likely disease-causing variants identified.(Circ Cardiovasc Genet. 2010;3:155-161.)

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

“…Several human genetics studies have reported dominant heterozygous mutations in MYH6 linked to hypertrophic cardiomyopathy, 35,36 DCM, 36,37 or CHD primarily consisting of secundum atrial septal defects. [38][39][40][41] To our knowledge, there has been no previous report of cardiomyopathy in patients with CHD who harbor a heterozygous MYH6 mutation.…”

“…Variable intrafamilial expression was also demonstrated in a family where 4 MYH6 mutation carriers had a range of phenotypes including bicuspid aortic valve, coarctation of the aorta, ventricular septal defect, and subaortic stenosis. 41 Assessment of 24 heterozygous MYH6 mutations associated with cardiomyopathy or a CHD revealed that 88% are private mutations identified in a single proband [35][36][37][38][39][40] and 63% are reported in the ExAC database 22 with allele frequencies that range from 0.00001 to 0.001. Because no information on cardiac phenotype is provided in the ExAC database, it is unknown whether screening echocardiography would reveal occult cardiomyopathy in carriers of these rare MYH6 alleles.…”

“…In fact, these allele frequencies are not dissimilar from those of previously reported heterozygous cardiomyopathy or CHD-associated MYH6 mutations (0.00001-0.001). [35][36][37][38][39][40][41] Even higher population-based allele frequencies have been identified in ExAC for heterozygous DCM-associated mutations in LDB3 (D117N; 0.0046) and CSRP3 (W4R;0.0024), both of which were functionally validated. [42][43][44][45] Compound heterozygosity for MYH6 mutations may be sufficient for arrested left heart development in the 1H and 4H probands, yet environmental factors could be contributory.…”

Heart Failure

“…When combined with our prior resequencing reports, Ϸ27% of DCM probands had possible or likely disease-causing variants identified. 29 …”

Dilated Cardiomyopathy

“…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.…”