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Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH
  1. K K Mantripragada1,
  2. A-C Thuresson2,
  3. A Piotrowski1,
  4. T Díaz de Ståhl1,
  5. U Menzel1,
  6. G Grigelionis1,
  7. R E Ferner3,
  8. S Griffiths4,
  9. L Bolund5,
  10. V Mautner6,
  11. M Nordling7,
  12. E Legius8,
  13. D Vetrie9,
  14. N Dahl2,
  15. L Messiaen10,
  16. M Upadhyaya4,
  17. C E G Bruder1,
  18. J P Dumanski1
  1. 1Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden
  2. 2Clinical Genetics, Uppsala University Children’s Hospital, 751 85 Uppsala, Sweden
  3. 3Department of Clinical Neurosciences, 2nd Floor Hodgkin Building, Guy’s, King’s, and St. Thomas’ School of Medicine, London Bridge, London, SE1 1UL, UK
  4. 4Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK
  5. 5Department of Human Genetics, University of Aarhus, Wilhelm Meyers Alle Bld. 240, 8000, Aarhus C, Denmark
  6. 6Department of Neurology, Klinikum Nord Ochsenzoll, Hamburg, Germany
  7. 7Department of Clinical Genetics, Gothenburg University, Sahlgrenska University Hospital East, SE-41685 Gothenburg, Sweden
  8. 8Center of Human Genetics, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
  9. 9The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB101SA, UK
  10. 10Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, AL, USA
  1. Correspondence to:
 Jan P Dumanski
 Department of Genetics and Pathology, Rudbeck Laboratory, Building C11, 3rd Floor, Uppsala University, 751 85 Uppsala, Sweden; jan.dumanski{at}


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 ∼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.

  • ANILFR, average normalised inter-locus fluorescence ratio
  • LCR, low copy repeat
  • LCR-D, LCR-distal
  • LCR-P, LCR-proximal
  • MLPA, multiplex ligation-dependent probe amplification
  • MPNST, malignant peripheral nerve sheath tumours
  • NF1, neurofibromatosis type 1
  • NPA, normalised peak area
  • UTR, untranslated region
  • array-CGH
  • malignant peripheral nerve sheath tumours
  • multiplex ligation-dependent probe amplification
  • neurofibromatosis type 1
  • segmental duplications

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  • Published Online First 8 June 2005

  • This work was supported by grants from the U.S. Army Medical Research and Materiel Command, award no. W81XWH-04-1-0269, the Swedish Cancer Foundation, Wallenberg Consortium North, The Swedish Research Council, and Uppsala University to JPD, and the Danish Platform for Integrated Biology of the Danish Basic Research Fund to LB

  • Competing interests: none declared