title: Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice.
abstract: BACKGROUND
  Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in individuals with mental retardation and congenital abnormality. Copy number variations (CNVs) are now readily detectable using a variety of platforms and a major challenge is the distinction of pathogenic from ubiquitous, benign polymorphic CNVs. The aim of this study was to investigate replacement of time consuming, locus specific testing for specific microdeletion and microduplication syndromes with microarray analysis, which theoretically should detect all known syndromes with CNV aetiologies as well as new ones.
  
  
  METHODS
  Genome wide copy number analysis was performed on 117 patients using Affymetrix 250K microarrays.
  
  
  RESULTS
  434 CNVs (195 losses and 239 gains) were found, including 18 pathogenic CNVs and 9 identified as "potentially pathogenic". Almost all pathogenic CNVs were larger than 500 kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity larger than 5 Mb were found in 5 patients.
  
  
  CONCLUSIONS
  Genome microarray analysis has improved diagnostic success in this group of patients. Several examples of recently discovered "new syndromes" were found suggesting they are more common than previously suspected and collectively are likely to be a major cause of mental retardation. The findings have several implications for clinical practice. The study revealed the potential to make genetic diagnoses that were not evident in the clinical presentation, with implications for pretest counselling and the consent process. The importance of contributing novel CNVs to high quality databases for genotype-phenotype analysis and review of guidelines for selection of individuals for microarray analysis is emphasised.
authors.affiliation: Cytogenetics Laboratory, Victorian Clinical Genetics Services/Pathology, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: D L
authors.initials: DL
authors.lastname: Bruno
authors.forename: D
authors.initials: D
authors.lastname: Ganesamoorthy
authors.forename: J
authors.initials: J
authors.lastname: Schoumans
authors.forename: A
authors.initials: A
authors.lastname: Bankier
authors.forename: D
authors.initials: D
authors.lastname: Coman
authors.forename: M
authors.initials: M
authors.lastname: Delatycki
authors.forename: R J M
authors.initials: RJ
authors.lastname: Gardner
authors.forename: M
authors.initials: M
authors.lastname: Hunter
authors.forename: P A
authors.initials: PA
authors.lastname: James
authors.forename: P
authors.initials: P
authors.lastname: Kannu
authors.forename: G
authors.initials: G
authors.lastname: McGillivray
authors.forename: N
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authors.lastname: Pachter
authors.forename: H
authors.initials: H
authors.lastname: Peters
authors.forename: C
authors.initials: C
authors.lastname: Rieubland
authors.forename: R
authors.initials: R
authors.lastname: Savarirayan
authors.forename: I E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: L
authors.initials: L
authors.lastname: Sheffield
authors.forename: T
authors.initials: T
authors.lastname: Tan
authors.forename: S M
authors.initials: SM
authors.lastname: White
authors.forename: A
authors.initials: A
authors.lastname: Yeung
authors.forename: Z
authors.initials: Z
authors.lastname: Bowman
authors.forename: C
authors.initials: C
authors.lastname: Ngo
authors.forename: K W
authors.initials: KW
authors.lastname: Choy
authors.forename: V
authors.initials: V
authors.lastname: Cacheux
authors.forename: L
authors.initials: L
authors.lastname: Wong
authors.forename: D J
authors.initials: DJ
authors.lastname: Amor
authors.forename: H R
authors.initials: HR
authors.lastname: Slater
mesh_terms: D020732:Cytogenetic Analysis; D018628:Gene Dosage; D020869:Gene Expression Profiling; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D019656:Loss of Heterozygosity; D046228:Microarray Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*