title: Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort.
abstract: OBJECTIVE
  Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing.
  
  
  METHODS
  Exon-focused arrays and whole-genome chromosomal microarray analysis were used to test 14,228 and 14,000 individuals, respectively. Based on these results, we developed an algorithm to detect deletions/duplications in whole-exome sequencing data and a novel whole-exome array.
  
  
  RESULTS
  In the exon array cohort, we observed a positive detection rate of 2.4% (25 duplications, 318 deletions), of which 39% involved one or two exons. Chromosomal microarray analysis identified 3,345 CNVs affecting single genes (18%). We demonstrate that our whole-exome sequencing algorithm resolves CNVs of three or more exons.
  
  
  CONCLUSIONS
  These results demonstrate the clinical utility of single-exon resolution in CNV assays. Our whole-exome sequencing algorithm approaches this resolution but is complemented by a whole-exome array to unambiguously identify intragenic CNVs and single-exon changes. These data illustrate the next advancements in CNV analysis through whole-exome sequencing and whole-exome array.Genet Med 17 8, 623-629.
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Kyle
authors.identifier: 0000000152522001
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Scuffins
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lewis
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pineda-Alvarez
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Stafford
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Schmidt
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Warren
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kondakova
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Blair
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Matyakhina
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Meck
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Swaroop
authors.initials: S
authors.lastname: Aradhya
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Eden
authors.initials: E
authors.lastname: Haverfield
mesh_terms: D000465:Algorithms; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D004247:DNA / Q000032:analysis / Q000097:blood / Q000235:genetics; D056915:DNA Copy Number Variations; D059472:Exome; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans
chemical_list: D004247:DNA