FMR1 Premutation Phenotypes in Population-Based & Clinically-Ascertained Samples

 描述（由申请人提供）：患有脆性 X 综合征 (FXS) 的儿童从其母亲那里继承了突变，几乎所有母亲都携带前突变 - 定义为 FMR1 基因中 55 - 200 个 CGG 重复。前突变携带者母亲已参与临床研究，据报道，她们患有运动、神经认知、健康和精神症状的风险升高，尽管对于这些症状是否是前突变表型的主要特征存在争议。或者，这些症状可能源于养育 FXS 突变儿童的压力。本申请提出的研究将促进对 FMR1 前突变表型的理解，由 Drs. 进行。来自威斯康星大学麦迪逊威斯曼中心、马什菲尔德诊所研究基金会和拉什大学医学中心的 Marsha Mailick、Jan S. Greenberg、Leann Smith、Elizabeth Berry-Kravis 和 Murray Brilliant。该项目将通过研究 344 名女性来表征 FMR1 前突变表型：(1) 从 20,000 人人口样本中抽取的 144 名女性构成了 Marshfield 诊所的个性化医学研究项目 (PMRP)，其中 72 名是前突变携带者（具有 55 至 190 CGG 扩展），但不知道自己的基因型，也没有诊断出 FXS 的孩子，以及72 个是匹配对照（< 41 个 CGG 重复）； (2) 200 名 FXS 完全突变儿童的前突变携带者母亲正在参与我们正在进行的研究和临床。至 据我们所知，这是第一项旨在包括基于人群的前突变女性样本（未从具有完全突变 FXS 的儿童中“反向确定”）以及临床确定的前突变女性的研究。因此，它提供了确定 FXS 完全突变儿童的前突变携带者母亲的表型特征是否代表人群中所有携带者的机会。我们的具体目标是：(1) 定义基于人群的样本中女性前突变携带者的运动、神经认知、健康和精神表型（不因了解其基因型或养育患有 FXS 的孩子而混淆），并确定表型在临床确定的样本中有何不同； (2)确定应激暴露对FMR1前突变携带者表型的影响； (3) 确定前突变携带者与年龄相关的症状特征。此外，我们将把 FMR1 前突变的基因型纳入分析中（CGG 重复长度、激活率以及 AGG 数量和位置），以确定基因型-表型相关性以及基因与环境之间的相互作用，以预测表型。我们组建了一支非常强大的跨学科科学家团队，其中包括在生物统计学、认知和发展心理学、流行病学、遗传学、神经病学、儿科、心理神经内分泌学和社会科学方面具有专业知识的科学家，以实现这些目标。

 DESCRIPTION (provided by applicant): Children with fragile X syndrome (FXS) inherit the mutation from their mothers, almost all of whom carry the premutation - defined as 55 - 200 CGG repeats in the FMR1 gene. Premutation carrier mothers have participated in clinical studies and have been reported to suffer from elevated risk of motor, neurocognitive, health, and psychiatric symptoms, although there is controversy regarding whether these symptoms are primary characteristics of the premutation phenotype. Alternatively, the symptoms could emanate from stressful parenting for a child with full mutation FXS. This application proposes research that will advance understanding of the FMR1 premutation phenotype, conducted by Drs. Marsha Mailick, Jan S. Greenberg, Leann Smith, Elizabeth Berry-Kravis, and Murray Brilliant from the University of Wisconsin-Madison Waisman Center, Marshfield Clinic Research Foundation, and Rush University Medical Center. The project will characterize the FMR1 premutation phenotype by studying 344 women: (1) 144 women drawn from a 20,000-person population-based sample who constitute the Personalized Medicine Research Project (PMRP) of the Marshfield Clinic, of whom 72 are premutation carriers (who have between 55 and 190 CGG expansions) but are unaware of their genotype and do not have children with diagnosed FXS, and 72 are matched controls (< 41 CGG repeats); and (2) 200 premutation carrier mothers of full mutation children with FXS who are participating in our ongoing studies and clinics. To the best of our knowledge, this is the first study designed to include both a population-based sample of women with the premutation who were not "reverse-ascertained" from a child with full-mutation FXS as well as clinically- ascertained women with the premutation. Thus, it offers the opportunity to determine whether the phenotypic characteristics of the premutation carrier mothers of full mutation children with FXS are representative of the full range of carriers in the population. Our Specific Aims are: (1) Define the motor, neurocognitive, health, and psychiatric phenotypes of female premutation carriers in a population-based sample (not confounded by knowledge of their genotype or parenting a child with FXS) and determine how the phenotype differs in a clinically-ascertained sample; (2) Determine the effect of stress exposure on the phenotype of FMR1 premutation carriers; and (3) Identify the age-related profile of symptoms in premutation carriers.. Additionally, we will incorporate the genotype of the FMR1 premutation into the analyses (CGG repeat length, activation ratio, and AGG number and location) to determine genotype-phenotype correlations and gene-by-environment interactions in predicting the phenotype. We have assembled an exceptionally strong interdisciplinary team of scientists including those with expertise in biostatistics, cognitive and developmental psychology, epidemiology, genetics, neurology, pediatrics, psychoneuroendocrinology, and social science to carry out these Aims.