title: Euchromatic 9q13-q21 duplication variants are tandem segmental amplifications of sequence reciprocal to 9q13-q21 deletions.
abstract: BACKGROUND
  There are four known pericentromeric euchromatic variants of chromosome 9 in the literature that are increasingly being observed in diagnostic cytogenetic laboratories. These variants pose diagnostic and counselling dilemmas, especially in prenatal settings, as distinction of a pathogenic alteration from a euchromatic variant is difficult. The molecular characterisation of three of these four variants has been reported. In this study, the genomic structure of the fourth variant, an additional G-positive band at 9q13-q21, is characterised.
  
  
  METHODS
  Two unrelated families with the 9q13-q21 duplication variant, and a third individual with a cytogenetically visible 9q13-q21 deletion, were studied using conventional and molecular cytogenetics techniques, as well as microarrays. The highly repetitive nature of the segmental duplications in the region also necessitated the use of both interphase and metaphase fluorescence in situ hybridisation (FISH).
  
  
  RESULTS
  It was determined that the DNA that constitutes this variant was ∼ 15-20 megabases in size and tandemly repeated as 3-4 cassettes of intrachromosomal segmental duplication. The variant appeared constitutively similar in sequence content and organisation between the two unrelated individuals, and it was inherited without apparent change. Sequences found amplified in the two duplication carriers were absent in the carrier of the deletion variant.
  
  
  CONCLUSIONS
  The sequences involved in both the 9q13-q21 duplication and deletion appear the same, implying reciprocity and suggesting non-allelic homologous recombination as the underlying mechanism. All four known euchromatic variants of chromosome 9 have now been shown to encompass segmental duplications. Importantly, a set of validated FISH probes was defined for the detection and characterisation of this 9q13-q21 amplification in the context of other chromosome 9 variants, allowing apparently benign variants to be distinguished from pathogenic changes.
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Joseph-George
authors.forename: Yongshu
authors.initials: Y
authors.lastname: He
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Raymond C C
authors.initials: RC
authors.lastname: Wong
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: MacDonald
authors.forename: Ciara A
authors.initials: CA
authors.lastname: Fahey
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Kathy
authors.initials: K
authors.lastname: Chun
authors.forename: Greg
authors.initials: G
authors.lastname: Ryan
authors.forename: Anne M
authors.initials: AM
authors.lastname: Summers
authors.forename: Elizabeth J T
authors.initials: EJ
authors.lastname: Winsor
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000328:Adult; D002872:Chromosome Deletion; D058674:Chromosome Duplication / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005333:Fetus; D005784:Gene Amplification / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D046228:Microarray Analysis