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Detailed mapping, mutation analysis, and intragenic polymorphism identification in candidate Noonan syndrome genes MYL2,DCN, EPS8, andRPL6
  1. A ION*,218,
  2. A H CROSBY*,218,
  3. H KREMER,218,
  5. M VAN REEN,218,
  6. C FENSKE*,218,
  7. I VAN DER BURGT,218,
  8. H G BRUNNER,218,
  9. K MONTGOMERY§,218,
  10. R S KUCHERLAPATI§,218,
  11. M A PATTON*,218,
  12. D C PAGE,
  13. E MARIMAN,218,
  14. S JEFFERY*,218
  1. *Medical Genetics Unit, St George's Medical School, Cranmer Terrace, Tooting, London SW17 ORE, UK
  2. †Department of Human Genetics, University Hospital Nijmegen, Geert Grooteplein 10, Nijmegen, The Netherlands
  3. ‡Department of Biochemistry, School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
  4. §Molecular Genetics Department, Albert Einstein College of Medicine, Bronx, New York, USA
  5. ¶Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  1. Dr Jeffery, sggt100{at}

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Editor—Noonan syndrome (NS) is an autosomal dominant developmental disorder in which the cardinal features include short stature, typical facies with hypertelorism, ptosis, downward slanting palpebral fissures, and low set, posteriorly rotated ears. In addition, there is a notable cardiac involvement seen in these patients, principally pulmonary valve stenosis and hypertrophic obstructive cardiomyopathy.1 2 The frequency of NS has been estimated to be between 1:1000-1:2500 live births.2 3

Using linkage analysis in a large three generation pedigree, we have previously mapped a gene for NS to an interval of more than 6 cM on 12q24 flanked by the markers D12S1637 andNOS1.4 5 A similar analysis in smaller two generation families showed genetic heterogeneity for this disorder.4 Despite the relatively high incidence of NS, there appears to be a distinct lack of large families suitable for linkage analysis, possibly resulting from an increase of infertility in males.6 However, the location of the NS gene has recently been further refined to a 5 cM interval through the identification of additional recombinants in one additional large NS family.7 No chromosome rearrangements associated with the disease have so far been discovered. In view of this, one approach currently being used to identify the underlying gene responsible for this disorder is examination of candidate genes from within this large region of chromosome 12. We present below the examination of four candidate genes, the precise localisation of three of which, epidermal growth factor receptor pathway substrate-8 (EPS8), decorin (DCN), and myosin light chain 2 (MYL2), had not previously been accurately determined. The fourth, ribosomal protein L6 (RPL6) was known to lie within the NS interval on 12q24.8

PCR was used to produce gene specific products for FISH (see below) and to produce exonic fragments for SSCP …

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  • 218 Members of the Noonan Syndrome Collaborative Group.