title: Use of high-throughput targeted exome-sequencing to screen for copy number variation in hypertrophic cardiomyopathy.
abstract: BACKGROUND
  The role of copy-number variants (CNV) as a cause of hypertrophic cardiomyopathy (HCM) is poorly studied. The aim of this study was to use high-throughput sequence (HTS) data combined with a read-depth strategy, to screen for CNV in cardiomyopathy-associated genes in a large consecutive cohort of HCM patients.
  
  
  METHODS
  Five-hundred-and-five unrelated HCM patients were genotyped using a HTS approach for 41 cardiovascular genes. We used a previously validated read-depth strategy (ExomeDepth) to call CNVs from the short-read sequence data. Detected CNVs in 19 cardiomyopathy-associated genes were then validated by comparative genomic hybridization array.
  
  
  RESULTS
  Twelve CNVs were identified. Four CNVs in 4 patients (0.8% of the cohort) were validated: one large deletion in MYBPC3, one large deletion in PDLIM3, one duplication of the entire TNNT2 gene and one large duplication in LMNA.
  
  
  CONCLUSIONS
  Our data suggest that the proportion of HCM cases with pathogenic CNVs is small (<1%). For the small subset of patients with clearly interpretable CNVs, our findings have direct clinical implications. Short read sequence data can be used for CNV calling, but the high false positive rate requires a validation step. The two-step strategy described here is effective at identifying novel genetic causes of HCM and similar techniques should be applied whenever possible.
authors.affiliation: Inherited Cardiovascular Disease Unit, Institute of Cardiovascular Science, UCL, London, UK; Cardiovascular Centre, University of Lisbon, Lisbon, Portugal.
authors.forename: L R
authors.initials: LR
authors.lastname: Lopes
authors.affiliation: UCL Genetics Institute, UCL, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Inherited Cardiovascular Disease Unit, Institute of Cardiovascular Science, UCL, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Syrris
authors.affiliation: Inherited Cardiovascular Disease Unit, Institute of Cardiovascular Science, UCL, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Dalageorgou
authors.affiliation: Inherited Cardiovascular Disease Unit, Institute of Cardiovascular Science, UCL, London, UK.
authors.forename: W J
authors.initials: WJ
authors.lastname: McKenna
authors.affiliation: Inherited Cardiovascular Disease Unit, Institute of Cardiovascular Science, UCL, London, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Elliott
authors.affiliation: UCL Genetics Institute, UCL, London, UK. Electronic address: v.plagnol@ucl.ac.uk.
authors.forename: V
authors.initials: V
authors.lastname: Plagnol
mesh_terms: D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D056915:DNA Copy Number Variations; D059472:Exome; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D020107:Troponin T / Q000235:genetics; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D020107:Troponin T; D000099163:Myosin Binding Protein C; C108834:PDLIM3 protein, human; C545568:TNNT2 protein, human
keywords: Copy number variants; High-throughput sequencing; Hypertrophic cardiomyopathy