Association of the Fragile X Premutation with Cognitive and Behavioral Skills in Children

脆性 X 前突变与儿童认知和行为技能的关联

基本信息

批准号：
10211231
负责人：
Tatyana Adayev
金额：
$ 64.64万
依托单位：
QUEENS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211231
关键词：
12 year old Address Adult Age Alleles Anxiety Anxiety Disorders Attention deficit hyperactivity disorder Attentional deficit Basic Science Behavioral CGG repeat Characteristics Child Child Behavior Child Rearing Childhood Clinical Cognitive Development Developmental Delay Disorders Developmental Disabilities Diagnosis Diagnostic Diagnostic Services Disease Emotional Evaluation Executive Dysfunction FMR1 FXTAS Family Family history of Fragile X Premutation Fragile X Syndrome Frequencies Genetic Screening Goals Health Health Personnel Healthcare Individual Inherited Institutes Intellectual functioning disability Interruption Intervention Interview Knowledge Late-Onset Disorder Length Life Link Literature Mathematics Measures Memory impairment Mental Depression Mental Health Mid-Atlantic Region Molecular Mothers Mutation Neurodevelopmental Deficit Neurodevelopmental Problem Neuropsychology New York Outcome Parents Participant Performance Phenotype Population Prenatal Diagnosis Prevalence Questionnaires Reading Recording of previous events Reporting Risk Risk Factors Sample Size School-Age Population Severities Short-Term Memory Siblings Standardization Stress Structure Surveys Testing Therapeutic Intervention Time Toxic effect Visuospatial Well in self Woman X Chromosome adverse outcome anxiety symptoms associated symptom autism spectrum disorder base behavioral pharmacology boys clinically significant cohort ethnic diversity executive function genetic information girls insight meetings multidisciplinary neurodevelopment neuropsychiatric disorder novel diagnostics prenatal prevent primary ovarian insufficiency proband prospective psychologic racial diversity sex skills social social deficits social skills

项目摘要

PROJECT SUMMARY The overarching goal of our proposal is to answer the clinically significant question: Does a fragile X premutation (PM; an allele of 55-200 CGG repeats in the X-linked FMR1 gene) pose a significant risk to childhood development? Why is this important? At least one in 300 women in the US carries a PM allele. Because most of these alleles are small and not prone to large expansions, nearly half of children born to these women will inherit a PM, whereas fewer than 6% will inherit a full mutation (>200 repeats), the allele that causes fragile X syndrome. PM alleles are known to increase the risk for two late-onset disorders: fragile X associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). Adults with a PM allele who do not have FXTAS or FXPOI are still reported to have executive skill and working memory deficits, visuospatial weakness and poor math skills, anxiety, and depression. For children who carry a PM, there is a significant gap in our knowledge. Some reports find higher rates of developmental delay, attention deficits, autism, and anxiety among children with a PM versus non-carriers, but these reports are limited by ascertainment bias and small sample size. We hypothesize that the toxic effect of a PM can manifest early in life, leading to adverse neurodevelopmental outcomes and we propose to test this rigorously and thoroughly. To address this gap in knowledge, we have an outstanding opportunity to study a large cohort of children, now age 3 -12 years, who were identified prospectively: specifically, 582 children with a PM and 958 non-carriers, all identified when their carrier mothers underwent prenatal diagnosis for a fragile X mutation. This unique cohort of children has minimal potential for ascertainment bias. In Aim 1, parents will complete online questionnaires to describe their child’s general health and history of diagnosed neurodevelopmental problems and to detail—using standardized questionnaires—the child’s behavior, executive skills, and social relatedness. In Aim 2, a subset of school-aged participants who live in the mid-Atlantic region will be assessed individually primarily via remote-administered semi-structured interview and neuropsychological measures examining cognitive, academic, social and psychological function. Mothers will also complete questionnaires regarding their own psychological well-being and parenting stress. We will evaluate all phenotypes with respect to sex, CGG repeat length, and repeat structure to gain insight into the mechanisms and associated risks (Aim 3). Our primary hypothesis is that children with a PM have a higher frequencies of neurodevelopmental deficits than non-carrier children, stratified by sex. The combination of parental report and direct assessment will provide a comprehensive evaluation of cognitive and behavioral skills. This will result in a powerful combination of detailed phenotypic and genetic information that will unambiguously define the risk of adverse childhood development posed by a PM allele.

项目摘要我们提案的总体目标是回答临床上重要的问题：易碎x是否脆弱 X连锁FMR1基因中的55-200 CGG重复等位基因（PM； PM的等位基因）对童年发展？为什么这很重要？在美国，至少有300名妇女有一个PM等位基因。因为这些等位基因中的大多数都很小，并且不容易扩张，所以几乎一半的孩子出生于这些女性将继承下午引起脆弱的X综合征。已知PM等位基因会增加两种晚发病的风险：脆弱x 相关的震颤/共济失调综合征（FXTA）和脆弱的X相关原发性卵巢不足（FXPOI）。据报道，患有没有FXTA或FXPOI的PM等位基因的成年人仍具有执行技巧和工作记忆定义，视觉弱点和数学技能差，焦虑和沮丧。适用于携带一个的孩子下午，我们的知识存在很大的差距。一些报告发现发育延迟率更高，患有PM与非携带者的儿童的注意力缺陷，自闭症和动画，但这些报告是受确定偏差和较小样本量的限制。我们假设PM的毒性作用可以表现出来在生命的早期，导致不良神经发育结果，我们建议严格测试这种结果为了解决这一知识差距，我们有一个很棒的机会来研究大量队列现年3 -12岁的孩子，他们被前瞻性地识别：具体来说，有582名PM和958的儿童非携带者，当他们的承运人母亲接受脆弱X突变的产前诊断时，所有载体都被确定。这种独特的儿童队列的确定性偏差潜力很小。在AIM 1中，父母将完成在线问卷描述孩子的一般健康和诊断神经发育史问题和详细说明 - 使用标准化问卷 - 孩子的行为，执行技能和社会相关性。在AIM 2中，将评估居住在中大西洋地区的一部分学龄参与者通过远程管理的半结构化访谈和神经心理学测量单独的主要原理检查认知，学术，社会和心理功能。母亲还将完成问卷调查考虑自己的心理健康和育儿压力。我们将评估所有表型尊重性别，CGG重复长度和重复结构，以深入了解机制和相关的机制风险（目标3）。我们的主要假设是，患有PM的儿童的频率较高神经发育定义的比非载体儿童定义，并通过性别分层。父母报告和直接评估将对认知和行为能力进行全面评估。这将导致详细的表型和遗传信息的强大组合，将明确定义风险 PM等位基因构成的不利儿童发展。