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

 描述(申请人提供)：患有脆性X综合征(FXS)的儿童遗传自他们的母亲，几乎所有的母亲都携带前突变-定义为FMR1基因中55-200个CGG重复。前突变携带者母亲参与了临床研究，并被报道患有运动、神经认知、健康和精神症状的风险增加，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，这些症状可能源于对携带全突变FXS的儿童的压力养育。这项申请提出的研究将促进对FMR1前突变表型的理解，由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的Marsha Mailick、Jan S.Greenberg、Leann Smith、Elizabeth Berry-Kravis和Murray Brilliant博士进行。该项目将通过研究344名妇女来表征FMR1前突变表型：(1)144名从20,000人人群样本中抽取的妇女，她们构成了马什菲尔德诊所的个性化医学研究计划(PMRP)，其中72人是预突变携带者(她们有55到190个CGG扩增)，但不知道自己的基因型别，也没有孩子确诊FXS，还有72人是匹配对照组(&lt；41个CGG重复序列)；以及(2)200名预突变携带者母亲，患有FXS的儿童，她们正在参与我们正在进行的研究和临床。发送到 据我们所知，这是第一项旨在同时包括基于人群的样本的研究，这些样本既包括没有从患有全突变FXS的儿童中“反向确定”的带有前突变的妇女，也包括临床确定的具有前突变的妇女。因此，它提供了一个机会来确定患有FXS的全突变儿童的前突变携带者母亲的表型特征是否代表了人群中所有的携带者。我们的具体目标是：(1)在人群样本中定义女性预突变携带者的运动、神经认知、健康和精神表型(不因了解她们的基因或养育患有FXS的孩子而困惑)，并确定在临床确定的样本中表型有何不同；(2)确定压力暴露对FMR1预突变携带者表型的影响；以及(3)确定预突变携带者中症状的年龄相关特征。此外，我们将把FMR1预突变的基因型纳入分析(CGG重复长度、激活比率、AGG数量和位置)，以确定在预测表型时的基因型-表型相关性和基因-环境交互作用。我们组建了一支非常强大的跨学科科学家团队，其中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长的科学家，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.