Phenotyping & genotype-phenotype correlations in NF1

描述（由申请人提供）：1型神经纤维瘤病是一种 常染色体显性遗传疾病，其标志性特征是良性 神经鞘肿瘤，神经纤维瘤。这种紊乱是一种典型的 变量表达式的示例，包括内部和之间的可变性 家庭可能的贡献者包括NF 1基因的等位基因异质性 突变，在不同的受影响的个体中不同，修改基因， 和随机因素。在这项研究中，我们打算确定遗传修饰剂， 使用最容易确定的NF 1表型，皮肤 神经纤维瘤和黑素斑，同时进行 详细定量评估NF 1表型的变异性及其 与NF 1突变类型的关系我们将测试NF 1的性质是否 在神经纤维瘤的顶部和底部10%中， number.我们还将使用不一致的同胞对策略来识别 修饰基因座，使用多态性微卫星标记，以测试是否 野生型NF 1等位基因作为其突变体效应的遗传修饰剂 配对，并通过单核苷酸多态性分析候选基因座 (SNP)分析.与此同时，我们将进行全面的定量分析， 一组独立的NF 1个体的表型分析。我们将聚集 关于皮肤神经纤维瘤数量的详细数据， caf-au-lait斑点，以及内部丛状的数量和位置 神经纤维瘤和脊髓神经纤维瘤，除了任何其他值得注意的NF 1 表型这些数据将为确定关系提供基础 不同的NF 1表型和NF 1突变，NF 1 野生型等位基因和修饰基因对表型变异的影响。的产品 这些研究，包括临床数据、遗传修饰分析结果、NF 1患者的永久细胞系和任何可用的肿瘤材料 将提供给研究界。遗传学解释 修饰因子、表型-表型相关性和基因型-表型 相关性在NF 1中都具有临床重要性， 预测个体有特定并发症风险的潜力，或避免 增加疾病进展风险的药物，并确定新的细胞 治疗的目标

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.