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Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11–17 distinct from the GAP related domain
  1. C Mattocks1,2,
  2. D Baralle1,4,
  3. P Tarpey1,3,
  4. C ffrench-Constant1,4,
  5. M Bobrow1,
  6. J Whittaker1
  1. 1Department of Medical Genetics, Box 134, Addenbrooke’s Hospital, Cambridge, UK
  2. 2Salisbury Reference Laboratory, UK
  3. 3The Wellcome Trust Sanger Centre, Hinxton, UK
  4. 4Department of Pathology, University of Cambridge, UK
  1. Correspondence to:
 Dr J Whittaker
 Regional Genetics Laboratories, Molecular Genetics, Kefford House, Maris Lane, Trumpington, Cambridge, CB2 2FF; joanne.whittakeraddenbrookes.nhs.uk

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Neurofibromatosis type 1 (NF1), formerly known as Von Recklinghausen Neurofibromatosis, is a common genetic disorder affecting approximately 1 in 3000–5000 people. It is a fully penetrant autosomal dominant disorder. Strict diagnostic criteria that include café au lait spots, neurofibromas, plexiform neurofibromas, freckling in the axillary or inguinal regions, Lisch nodules (iris haematomas), optic or chiasma glioma, pseudoarthrosis, and sphenoid dysplasia define NF1. Most disease features are present in more than 90% of patients at puberty.1 Further manifestations are known to occur in this disorder, including macrocephaly, short stature, learning difficulties, scoliosis and certain malignancies.2–4 There is, however, great intra and interfamilial phenotypic variability. In addition a number of patients who have a clinical picture suspected to be NF1 do not fulfil the diagnostic criteria particularly in the younger age groups. As a consequence genetic testing would have a major impact on the diagnosis and management of these families.

The NF1 gene maps to chromosome 17q11.2 and is thought to be a tumour suppressor gene because loss of heterozygosity is associated with the occurrence of benign and malignant tumours in tissues derived from the neural crest5–7 as well as myeloid malignancies.8 It spans a region of about 350 kb of genomic DNA and contains 60 exons.9–11 It harbours at least three other embedded genes—EV12A, EV12B, and ONGP—transcribed from the opposite strand of NF1 intron 27b. The NF1 gene transcribes several mRNAs in the size range 11–13 kb expressed in neurones, oligodendrocytes and non-myelinating Schwann cells.12 The most common transcript codes for a polypeptide of 2818 amino acids called neurofibromin.13–15 A 360 amino acid region of the predicted protein product shows homology with the GTPase activating (GAP) family of proteins in yeast and mammals.16 The GAP related domain (GRD) is …

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