title: Population-based variation in cardiomyopathy genes.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy and dilated cardiomyopathy arise from mutations in genes encoding sarcomere proteins including MYH7, MYBPC3, and TTN. Genetic diagnosis of cardiomyopathy relies on complete sequencing of the gene coding regions, and most pathogenic variation is rare. The 1000 Genomes Project is an ongoing consortium designed to deliver whole genome sequence information from an ethnically diverse population and, therefore, is a rich source to determine both common and rare genetic variants.
  
  
  RESULTS
  We queried the 1000 Genomes Project database of 1092 individuals for exonic variants within 3 sarcomere genes MHY7, MYBPC3, and TTN. We focused our analysis on protein-altering variation, including nonsynonymous single nucleotide polymorphisms, insertion/deletion polymorphisms, or splice site altering variants. We identified known and predicted pathogenic variation in MYBPC3 and MYH7 at a higher frequency than what would be expected based on the known prevalence of cardiomyopathy. We also found substantial variation, including protein-disrupting sequences, in TTN.
  
  
  CONCLUSIONS
  Cardiomyopathy is a genetically heterogeneous disorder caused by mutations in multiple genes. The frequency of predicted pathogenic protein-altering variation in cardiomyopathy genes suggests that many of these variants may be insufficient to cause disease on their own but may modify phenotype in a genetically susceptible host. This is suggested by the high prevalence of TTN insertion/deletions in the 1000 Genomes Project cohort. Given the possibility of additional genetic variants that modify the phenotype of a primary driver mutation, broad-based genetic testing should be employed.
authors: Department of Medicine and Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors: Jessica R
authors: JR
authors: Golbus
authors: Megan J
authors: MJ
authors: Puckelwartz
authors: John P
authors: JP
authors: Fahrenbach
authors: Lisa M
authors: LM
authors: Dellefave-Castillo
authors: Don
authors: D
authors: Wolfgeher
authors: Elizabeth M
authors: EM
authors: McNally
mesh_terms: D024722:Cardiac Myosins / Q000235:genetics; D009202:Cardiomyopathies / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D064211:Connectin; D030541:Databases, Genetic; D016368:Frameshift Mutation / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D044469:Racial Groups / Q000235:genetics; D012518:Sarcomeres / Q000235:genetics; D000099163:Myosin Binding Protein C
chemical_list: D024722:Cardiac Myosins; D002352:Carrier Proteins; D064211:Connectin; D009124:Muscle Proteins; D018995:Myosin Heavy Chains; D011494:Protein Kinases; D000099163:Myosin Binding Protein C; C501641:MYH7 protein, human; C577285:TTN protein, human