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

基于人群的 FMR1 前突变表型

基本信息

批准号：
9505945
负责人：
MARSHA RUTH MAILICK
金额：
$ 52.91万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9505945
关键词：
Academic Medical Centers Adenine Adult Affect Age Alleles Anxiety Ataxia Autoimmune Diseases Awareness Berry Biometry Caring Characteristics Child Child Rearing Clinic Clinical Clinical Research Cognitive Science Cytosine DNA Dementia Diagnosis Epidemiology Evaluation Exposure to FMR1 FMR1 Premutation FXTAS Family Female Foundations Fragile X Syndrome Genetic Genetic Status Genotype Guanine Health Heterogeneity High Prevalence Impaired cognition Individual Inherited Knowledge Lead Length Literature Location Measures Medical Mental Depression Methods Mothers Motor Mutation Neonatal Screening Nerve Degeneration Neurocognitive Neurology Neuropathy Parkinsonian Disorders Patients Pediatrics Persons Phenotype Population Population Study Prevalence Psychoneuroendocrinology Public Health Reporting Research Research Design Research Project Grants Rest Risk Sampling Scientist Severities Social Sciences Specific qualifier value Stress Subgroup Symptoms Syndrome Tremor Universities Wisconsin Woman Women&apos s Group Work age related base clinical practice clinical risk cohort developmental psychology gene environment interaction human disease insight member personalized medicine policy implication population based premature primary ovarian insufficiency psychiatric symptom public health relevance repository reproductive senescence resilience

项目摘要

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.

描述（由适用提供）：患有脆弱X综合征（FXS）的儿童从母亲那里继承了突变，几乎所有携带预先享用的人 - 定义为FMR1基因中的55-200 CGG重复。预先享有的载体母亲已经参加了临床研究，据报道，运动，神经认知，健康和精神病症状的风险升高，尽管这些症状是否是预先享有表型的主要特征存在争议。另外，症状可能会从全面突变FXS的儿童压力育儿中散发出来。该应用程序提出的研究将提高对DRS进行的FMR1预先享有的表型的理解。 Marsha Mailick，Jan S. Greenberg，Leann Smith，Elizabeth Berry-Kravis和Wisconsin-Madison Waisman Center，Marshfield Clinic Research Foundation和Rush University Medical Center的Murray Brilther。该项目将通过研究344名妇女来表征FMR1预先享有的表型：（1）144名女性来自20,000个基于人群的样本，这些样本构成了Marshfield诊所的个性化医学研究项目（PMRP），其中72个是Premaintriers（其中有55至190 CGG扩展），但没有诊断为55至190 CGG的控制。 41 CGG重复）；（2）有200名全面突变儿童有FXS的首映载体母亲正在参加我们正在进行的研究和诊所。到我们最了解的是，这是第一项研究，旨在包括一个基于人群的女性样本，这些妇女的妇女并未从具有全妇女的FXS以及临床确定的具有首映的妇女“反向确定”。这是一个机会，可以确定有FXS的完整突变儿童的预先携带携带者母亲的表型特征是否代表了人口中的全部携带者。我们的具体目的是：（1）在基于人群的样本中定义女性预登机携带者的运动，神经认知，健康和精神病表型（不与知识的基因型知识或使用FXS育儿相混淆），并确定表型在临床范围的样本中的差异；（2）确定压力暴露对FMR1预先携带载体表型的影响；（3）确定符号在预先载体中的年龄相关谱。我们组建了一个非常强大的科学家跨学科团队，包括那些在生物统计学，认知和发育心理学，流行病学，遗传学，神经病学，儿科，心理术语内分泌学和社会科学方面具有专业知识的人。