title: Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH.
abstract: BACKGROUND
  Segmental duplications flanking the neurofibromatosis type 1 (NF1) gene locus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report the construction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11, using a non-redundant approach for array design. The average resolution of analysis for the array is approximately 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1 gene.
  
  
  METHODS
  We performed a comprehensive array-CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in 26 cases, whereas 13 samples showed atypical deletion profiles.
  
  
  RESULTS
  The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of the deletion. The deletions identified by array-CGH were independently confirmed using multiplex ligation-dependent probe amplification. Bioinformatic analysis of the entire locus identified 33 segmental duplications.
  
  
  CONCLUSIONS
  We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.
authors.affiliation: Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: K K
authors.initials: KK
authors.lastname: Mantripragada
authors.forename: A-C
authors.initials: AC
authors.lastname: Thuresson
authors.forename: A
authors.initials: A
authors.lastname: Piotrowski
authors.forename: T
authors.initials: T
authors.lastname: Díaz de Ståhl
authors.forename: U
authors.initials: U
authors.lastname: Menzel
authors.forename: G
authors.initials: G
authors.lastname: Grigelionis
authors.forename: R E
authors.initials: RE
authors.lastname: Ferner
authors.forename: S
authors.initials: S
authors.lastname: Griffiths
authors.forename: L
authors.initials: L
authors.lastname: Bolund
authors.forename: V
authors.initials: V
authors.lastname: Mautner
authors.forename: M
authors.initials: M
authors.lastname: Nordling
authors.forename: E
authors.initials: E
authors.lastname: Legius
authors.forename: D
authors.initials: D
authors.lastname: Vetrie
authors.forename: N
authors.initials: N
authors.lastname: Dahl
authors.forename: L
authors.initials: L
authors.lastname: Messiaen
authors.forename: M
authors.initials: M
authors.lastname: Upadhyaya
authors.forename: C E G
authors.initials: CE
authors.lastname: Bruder
authors.forename: J P
authors.initials: JP
authors.lastname: Dumanski
mesh_terms: D019457:Chromosome Breakage; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D025542:Neurofibromin 1 / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results
chemical_list: D025542:Neurofibromin 1