title: 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 >30 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.
  
  
  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 (alpha-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 (n=33; 10.6% overall). One MYH6 variant was classified as unlikely to be disease causing.
  
  
  CONCLUSIONS
  Rare variants in these 5 genes likely or possibly caused 10.6% of DCM in this cohort. When combined with our prior resequencing reports, approximately 27% of DCM probands had possible or likely disease-causing variants identified.
authors.affiliation: University of Miami Miller School of Medicine, Fla. 33136, USA. rhershberger@med.miami.edu <rhershberger@med.miami.edu>
authors.forename: Ray E
authors.initials: RE
authors.lastname: Hershberger
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.forename: Ana
authors.initials: A
authors.lastname: Morales
authors.forename: Duanxiang
authors.initials: D
authors.lastname: Li
authors.forename: Jill D
authors.initials: JD
authors.lastname: Siegfried
authors.forename: Jorge
authors.initials: J
authors.lastname: Gonzalez-Quintana
mesh_terms: D019943:Amino Acid Substitution; D024722:Cardiac Myosins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D006239:Haplotypes; D006801:Humans; D018995:Myosin Heavy Chains / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D017422:Sequence Analysis, DNA; D014335:Tropomyosin / Q000235:genetics*; D019209:Troponin C / Q000235:genetics*; D019210:Troponin I / Q000235:genetics*; D000099163:Myosin Binding Protein C
chemical_list: D024722:Cardiac Myosins; D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D014335:Tropomyosin; D019209:Troponin C; D019210:Troponin I; D000099163:Myosin Binding Protein C; C094239:MYH6 protein, human; C490775:TPM1 protein, human