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

项目总结 我们建议的首要目标是回答一个具有临床意义的问题：脆性X 预突变(PM；X连锁FMR1基因中55-200个CGG重复的等位基因)对 童年发展？为什么这很重要？在美国，至少每300名女性中就有一名携带PM等位基因。 因为这些等位基因中的大多数都很小，而且不容易大幅扩张，所以出生时患有癌症的儿童中有近一半 这些女性将继承PM，而不到6%的女性将继承完全突变(&gt；200重复)，即 导致脆性X综合征。已知PM等位基因会增加两种迟发性疾病的风险：脆性X 相关震颤/共济失调综合征(FXTAS)和脆性X相关的原发卵巢功能不全(FXPOI)。 据报道，没有FXTAS或FXPOI的PM等位基因的成年人仍然具有执行技能和工作能力 记忆力减退、视觉空间薄弱、数学能力差、焦虑和抑郁。适用于携带 PM，我们的知识有一个很大的差距。一些报告发现，发育迟缓率更高， PM携带者与非携带者儿童之间的注意力缺陷、自闭症和焦虑，但这些报告是 受确定偏差和样本量小的限制。我们假设首相的毒害效应可以表现出来 在生命早期，会导致不良的神经发育结果，我们建议对此进行严格的测试和 彻底地。为了解决这一知识差距，我们有一个绝佳的机会来研究一大批 现在3-12岁的儿童，被前瞻性识别：具体地说，582名患有PM的儿童和958名儿童 非携带者，当他们的携带者母亲接受脆性X突变的产前诊断时都被识别出来。 这一独特的儿童群体具有最小的确定偏见的可能性。在目标1中，家长将完成 在线问卷，描述孩子的一般健康状况和确诊的神经发育病史 问题和细节--使用标准化问卷--儿童的行为、执行技能和社交能力 关联性。在目标2中，将评估居住在大西洋中部地区的一部分学龄儿童参与者 个人，主要是通过远程管理的半结构访谈和神经心理测量 考察认知、学术、社会和心理功能。母亲们还将完成问卷调查 关注自己的心理健康和育儿压力。我们将对所有表型进行评估 尊重性别、CGG重复长度和重复结构，以获得对机制和相关的洞察 风险(目标3)。我们的主要假设是患有多发性硬化症的儿童有更高的 神经发育缺陷的儿童比非携带者儿童，按性别分层。家长报告与家长报告相结合 直接评估将提供对认知和行为技能的全面评估。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 由PM等位基因造成的儿童不良发育。

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.