title: An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.
abstract: OBJECTIVE
  Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care.
  
  
  METHODS
  A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions.
  
  
  RESULTS
  Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic.
  
  
  CONCLUSIONS
  Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Kaminsky
authors.forename: Vineith
authors.initials: V
authors.lastname: Kaul
authors.forename: Justin
authors.initials: J
authors.lastname: Paschall
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Church
authors.forename: Brian
authors.initials: B
authors.lastname: Bunke
authors.forename: Dawn
authors.initials: D
authors.lastname: Kunig
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreno-De-Luca
authors.forename: Andres
authors.initials: A
authors.lastname: Moreno-De-Luca
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Mulle
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: John G
authors.initials: JG
authors.lastname: Compton
authors.forename: Amy E
authors.initials: AE
authors.lastname: Fuller
authors.forename: Troy J
authors.initials: TJ
authors.lastname: Gliem
authors.forename: Shuwen
authors.initials: S
authors.lastname: Huang
authors.forename: Morag N
authors.initials: MN
authors.lastname: Collinson
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Beal
authors.forename: Todd
authors.initials: T
authors.lastname: Ackley
authors.forename: Diane L
authors.initials: DL
authors.lastname: Pickering
authors.forename: Denae M
authors.initials: DM
authors.lastname: Golden
authors.forename: Emily
authors.initials: E
authors.lastname: Aston
authors.forename: Heidi
authors.initials: H
authors.lastname: Whitby
authors.forename: Shashirekha
authors.initials: S
authors.lastname: Shetty
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rossi
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Rudd
authors.forename: Sarah T
authors.initials: ST
authors.lastname: South
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Brothman
authors.forename: Warren G
authors.initials: WG
authors.lastname: Sanger
authors.forename: Ramaswamy K
authors.initials: RK
authors.lastname: Iyer
authors.forename: John A
authors.initials: JA
authors.lastname: Crolla
authors.forename: Erik C
authors.initials: EC
authors.lastname: Thorland
authors.forename: Swaroop
authors.initials: S
authors.lastname: Aradhya
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.forename: Christa L
authors.initials: CL
authors.lastname: Martin
mesh_terms: D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics*; D019317:Evidence-Based Medicine / Q000379:methods*; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*