Phenotyping & genotype-phenotype correlations in NF1

描述(申请人提供)：1型神经纤维瘤病是一种 常染色体显性遗传病，其特点是发生良性 神经鞘肿瘤，神经纤维瘤。这种障碍是一种典型的 变量表达式示例，包括内部和之间的可变性 家人。可能的因素包括nf1基因的等位基因异质性。 突变，在不同的受影响个体之间有所不同，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物 使用最容易确定的NF1表型，皮肤 神经纤维瘤和咖啡馆斑点，同时进行 NF1表型及其变异性的详细定量评估 与NF1突变类型的关系。我们将测试NF1的性质是否 神经纤维瘤顶部和底部10%的突变在不同的个体中不同 数。我们还将使用不协调的同胞对策略来识别 修饰性基因座，使用多态微卫星标记来测试 野生型NF1等位基因作为其突变效应的遗传修饰物 并用单核苷酸多态分析候选基因座 (SNP)分析。同时，我们将全面量化 一组患有NF1的独立个体的表型。我们会齐聚一堂 关于皮肤神经纤维瘤数量的详细数据， 内丛的斑点、数量和位置 神经纤维瘤和脊髓神经纤维瘤，以及任何其他值得注意的NF1 表型。这些数据将为定义关系提供基础 不同NF1表型之间的关系及NF1突变的贡献 野生型等位基因和对表型变异的修饰基因。的产品 这些研究包括临床数据、遗传修饰物分析结果、来自NF1患者的永久细胞系以及任何可用的肿瘤材料 将向研究界提供。基因的阐明 修饰因子、表型-表型相关性和基因-表型 在NF1中，相关性都将具有临床重要性，如果 有可能预测有特定并发症风险的个体，或避免 增加疾病进展风险的药物，并识别新的细胞 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.