title: Identification of copy number variants from exome sequence data.
abstract: BACKGROUND
  With advances in next generation sequencing technologies and genomic capture techniques, exome sequencing has become a cost-effective approach for mutation detection in genetic diseases. However, computational prediction of copy number variants (CNVs) from exome sequence data is a challenging task. Whilst numerous programs are available, they have different sensitivities, and have low sensitivity to detect smaller CNVs (1-4 exons). Additionally, exonic CNV discovery using standard aCGH has limitations due to the low probe density over exonic regions. The goal of our study was to develop a protocol to detect exonic CNVs (including shorter CNVs that cover 1-4 exons), combining computational prediction algorithms and a high-resolution custom CGH array.
  
  
  RESULTS
  We used six published CNV prediction programs (ExomeCNV, CONTRA, ExomeCopy, ExomeDepth, CoNIFER, XHMM) and an in-house modification to ExomeCopy and ExomeDepth (ExCopyDepth) for computational CNV prediction on 30 exomes from the 1000 genomes project and 9 exomes from primary immunodeficiency patients. CNV predictions were tested using a custom CGH array designed to capture all exons (exaCGH). After this validation, we next evaluated the computational prediction of shorter CNVs. ExomeCopy and the in-house modified algorithm, ExCopyDepth, showed the highest capability in detecting shorter CNVs. Finally, the performance of each computational program was assessed by calculating the sensitivity and false positive rate.
  
  
  CONCLUSIONS
  In this paper, we assessed the ability of 6 computational programs to predict CNVs, focussing on short (1-4 exon) CNVs. We also tested these predictions using a custom array targeting exons. Based on these results, we propose a protocol to identify and confirm shorter exonic CNVs combining computational prediction algorithms and custom aCGH experiments.
authors.forename: Pubudu Saneth
authors.initials: PS
authors.lastname: Samarakoon
authors.forename: Hanne Sørmo
authors.initials: HS
authors.lastname: Sorte
authors.forename: Bjørn Evert
authors.initials: BE
authors.lastname: Kristiansen
authors.forename: Tove
authors.initials: T
authors.lastname: Skodje
authors.forename: Ying
authors.initials: Y
authors.lastname: Sheng
authors.forename: Geir E
authors.initials: GE
authors.lastname: Tjønnfjord
authors.forename: Barbro
authors.initials: B
authors.lastname: Stadheim
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.forename: Olaug Kristin
authors.initials: OK
authors.lastname: Rødningen
authors.affiliation: Department of Medical Genetics, University of Oslo, Oslo, Norway. Robert.Lyle@medisin.uio.no.
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
mesh_terms: D000465:Algorithms; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis
references.citation: Genomics. 2007 May;89(5):647-53
references.pmid: 17276656
references.citation: Bioinformatics. 2012 Nov 1;28(21):2747-54
references.pmid: 22942019
references.citation: Nat Methods. 2012 Apr 27;9(5):459-62
references.pmid: 22543379
references.citation: Nat Genet. 2011 Mar;43(3):269-76
references.pmid: 21317889
references.citation: Hum Mutat. 2008 Jan;29(1):159-66
references.pmid: 17924555
references.citation: Nat Rev Genet. 2011 Sep 27;12(11):745-55
references.pmid: 21946919
references.citation: Nat Genet. 2011 May;43(5):491-8
references.pmid: 21478889
references.citation: Bioinformatics. 2011 Oct 1;27(19):2648-54
references.pmid: 21828086
references.citation: Bioinformatics. 2012 May 15;28(10):1307-13
references.pmid: 22474122
references.citation: Am J Hum Genet. 2012 Oct 5;91(4):597-607
references.pmid: 23040492
references.citation: Hum Mutat. 2013 Oct;34(10):1439-48
references.pmid: 23893877
references.citation: Genome Res. 2012 Aug;22(8):1525-32
references.pmid: 22585873
references.citation: Genome Res. 2012 Sep;22(9):1760-74
references.pmid: 22955987
references.citation: Stat Appl Genet Mol Biol. 2011 Nov 08;10(1):
references.pmid: 23089826
references.citation: Bioinformatics. 2007 Mar 15;23(6):657-63
references.pmid: 17234643