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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：
9134762
负责人：
MARSHA RUTH MAILICK
金额：
$ 59.68万
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 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134762
关键词：
Academic Medical Centers Adenine Adult Affect Age Alleles Anxiety Ataxia Autoimmune Diseases Berry Biometry Caring Characteristics Child Child Rearing Clinic Clinical Clinical Research Cognitive Science Cytosine DNA Dementia Diagnosis Evaluation Exposure to FMR1 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 Neuropathy Parkinsonian Disorders Patients Pediatric Neurology Persons Phenotype Population 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 genetic epidemiology 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.