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Neurofibromatosis type 1 is one ofthe most common inherited disorders with an incidence of 1 in 3000. The search for NFI mutations has been hampered by the overall size of the gene, the large number of exons, and the high mutation rate. To date, fewer than 90 mutations have been reported to the NFI mutation analysis consortium and the details on 76 mutations have been published.We have identified five new mutations using single strand conformation polymorphism (SSCP) and heteroduplex analysis (HA) and three intragenic deletions with the microsatellite markers. Of the five new mutations, two were in exon 27a, two in exon 45, and one in exon 49 and these include 4630delA, 4572delC, R7846X, T7828A, and one in the 3' untranslated region (3' UTR). The two nucleotide alterations in exon 27a and the one in exon 45 are predicted to produce a truncated protein. (JMed Genet 1995;32:706-710) Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders with a birth frequency of approximately 1 in 3000. The disease is characterised by cafe au lait spots, neurofibromas, and Lisch nodules (hamartomas of the iris). NF 1 has many complications which include complex neurocognitive difficulties, plexiform neurofibromas, and an increased risk of specific types of malignancy.'The NF1 gene is more than 300 kb in size, consists of 59 exons, and has been mapped to 17qll.2.2-5 The NFI transcript encodes a protein, neurofibromin, which is related to a number of GTPase activating proteins (GAP) and is involved in the negative control of ras mediated signal transduction.6 Neurofibromin also appears to be associated with cytoplasmic microtubules. This association between ras mediated signal transduction and the cytoskeleton suggests that neurofibromin may play multiple roles in the regulation of cell division.7The NF 1 mutation rate, approximately 1 x 10-4/gamete/generation,' is the highest described for any human disorder, and is some 100 fold higher than that usually found at a single locus, with the result that almost half of all cases of NF I represent new mutations. This high mutation rate could either be because of the large size of the NFl gene or the presence of highly mutable sequences within the gene.The identification and characterisation of disease specific mutations in the NFl gene should enable one to detect such mutational "hot spots" for mutations and to study correlation between the genotype and phenotype. The search for NF1 mutations has been hampered by the overall size of the gene and the large number of exons. To date fewer than 90 mutations have been reported to the NF1 mutation analysis consortium,9 and details of only 76 of these mutations have been published.'0 We have previously reported the identification of 14 mutations within the NFl gene." '-14 We have since expanded our study to screen for NF1 gene mutations within exons 27a, 45, and 49 and here describe five new mutations identified by single strand conformation polymorphism (SSCP) analysis and heteroduplex analysis (HA). Three int...

The fragile X syndrome is the most common cause of familial mental retardation. Genetic counseling and gene isolation are hampered by a lack of DNA markers close to the disease locus. Two somatic cell hybrids that each contain a human X chromosome with a breakpoint close to the fragile X locus have been characterized. A new DNA marker (DXS296) lies between the chromosome breakpoints and is the closest marker to the fragile X locus yet reported. The Hunter syndrome gene, which causes iduronate sulfatase deficiency, is located at the X chromosome breakpoint that is distal to this new marker, thus localizing the Hunter gene distal to the fragile X locus.

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DNA samples were obtained from children with