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

 描述（申请人提供）：脆性X综合征（FXS）的儿童从母亲那里遗传了突变，几乎所有的母亲都携带前突变-定义为FMR 1基因中的55 - 200个CGG重复。前突变携带者的母亲参加了临床研究，并已报告患有运动，神经认知，健康和精神症状的风险增加，尽管这些症状是否是前突变表型的主要特征存在争议。或者，这些症状可能来自于对FXS完全突变儿童的压力养育。本申请提出的研究将促进对FMR 1前突变表型的理解，由玛莎·梅里克博士，扬·S·。格林伯格、利恩·史密斯、伊丽莎白·贝里·克拉维斯和默里·布里连特来自威斯康星大学麦迪逊韦斯曼中心、马什菲尔德临床研究基金会和拉什大学医学中心。该项目将通过研究344名女性来表征FMR 1前突变表型：（1）从20，000人的人群样本中抽取的144名女性，这些样本构成了马什菲尔德诊所的个性化医学研究项目（PMRP），其中72人是前突变携带者（CGG扩增在55到190之间），但不知道他们的基因型，没有诊断为FXS的孩子，72人是匹配的对照组。（< 41 CGG重复）;和（2）200名参与我们正在进行的研究和诊所的FXS全突变儿童的前突变携带者母亲。到 据我们所知，这是第一个设计成包括未从具有全突变FXS的儿童“反向确定”的具有前突变的妇女的基于人群的样本以及临床确定的具有前突变的妇女的研究。因此，它提供了一个机会，以确定是否前突变携带者的母亲的FXS全突变儿童的表型特征是在人口中的所有范围的运营商的代表。我们的具体目标是：（1）在基于人群的样本中定义女性前突变携带者的运动、神经认知、健康和精神病表型（2）确定应激暴露对FMR 1前突变携带者表型的影响;和（3）确定前突变携带者与年龄相关的症状谱。此外，我们还将FMR 1前突变的基因型纳入分析（CGG重复长度、激活率和AGG数量和位置），以确定基因型-表型相关性和预测表型的基因-环境相互作用。我们已经组建了一支非常强大的跨学科科学家团队，包括那些在生物统计学，认知和发展心理学，流行病学，遗传学，神经学，儿科学，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.