Phenotyping & genotype-phenotype correlations in NF1

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DESCRIPTION (provided by the applicant): Neurofibromatosis type 1 is an autosomal dominant disorder whose hallmark feature is the occurrence of benign tumors of the nerve sheath, neurofibromas. The disorder is a paradigmatic example of variable expression, including variability both within and between families. Possible contributors include allelic heterogeneity of the NF1 gene mutations, which differ among different affected individuals, modifying genes, and stochastic factors. In this study, we intend to identify genetic modifiers of NF1 using the most readily determined NF1 phenotypes, cutaneous neurofibromas and cafe-au-lait spots, while simultaneously carrying out a detailed quantitative assessment of the variability of NF1 phenotypes and its relationship to NF1 mutation type. We will test whether the nature of the NF1 mutation differs in individuals in the top and bottom 10% for neurofibroma number. We will also use a discordant sib-pair strategy for identification of modifier loci, using polymorphic microsatellite markers to test whether the wild-type NF1 allele acts as a genetic modifier of the effects of its mutant counterpart, and analyzing candidate loci by single nucleotide polymorphism (SNP) analysis. In parallel, we will perform comprehensive quantitative phenotyping of a cohort of independent individuals with NF1. We will gather detailed data concerning numbers of dermal neurofibromas, number of café-au-lait spots, and number and location of internal plexiform neurofibromas and spinal neurofibromas, in addition to any other notable NF1 phenotypes. These data will provide the basis for defining the relationship between different NF1 phenotypes and the contribution of NF1 mutation, NF1 wild-type allele and modifier genes to variation in phenotype. The products of these studies, including clinical data, results of genetic modifier analyses, permanent cell-lines from the NF1 patients, and any available tumor material will be made available to the research community. Elucidation of genetic modifiers, phenotype-phenotype correlations, and genotype-phenotype correlations would all be of clinical importance in NF1, providing the potential to predict individuals at risk of specific complications, or to avoid agents that increase risk of disease progression, and identifying new cellular targets for therapy.