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

项目摘要 我们的建议的首要目标是回答临床上重要的问题： 前突变（PM; X连锁FMR 1基因中55-200 CGG重复的等位基因）对以下疾病构成显著风险： 儿童发展？为什么这很重要？在美国，每300名女性中至少有一名携带PM等位基因。 因为这些等位基因大多数都很小，不容易大规模扩增， 这些女性将遗传PM，而不到6%的人将遗传完整突变（>200个重复），即 会导致脆性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染色体 相关震颤/共济失调综合征（FXTAS）和脆性X相关原发性卵巢功能不全（FXPOI）。 没有FXTAS或FXPOI的携带PM等位基因的成年人仍然被报道具有执行技能和工作能力。 记忆缺陷、视觉空间缺陷和数学能力差、焦虑和抑郁。对于携带 PM，我们的知识有很大的差距。一些报告发现发育迟缓的比率更高， 注意力缺陷，自闭症和焦虑症的儿童与非携带者，但这些报告是 受确定偏差和小样本量的限制。我们假设PM的毒性作用可以表现为 在生命的早期，导致不利的神经发育结果，我们建议严格测试这一点， 彻底为了解决这一知识差距，我们有一个很好的机会来研究一个大的队列， 前瞻性确定的3 - 12岁儿童：具体来说，582名患有PM的儿童和958名患有PM的儿童 非携带者，都是在其携带者母亲接受脆性X突变产前诊断时确定的。 这个独特的儿童队列具有最小的确定偏倚的可能性。在目标1中，父母将完成 在线问卷调查，以描述他们的孩子的一般健康状况和诊断的神经发育史 问题和细节-使用标准化的工具-孩子的行为，执行技能，和社会 相关性在目标2中，将评估居住在大西洋中部地区的学龄参与者的子集 主要通过远程管理的半结构化访谈和神经心理学测量进行个人评估 检查认知、学术、社会和心理功能。母亲们也将完成调查问卷 关于他们自己的心理健康和养育压力。我们将评估所有表型， 性别、CGG重复序列长度和重复序列结构，以深入了解其机制和相关的 风险（目标3）。我们的主要假设是，患有PM的儿童有更高的 神经发育缺陷比非携带者儿童，按性别分层。父母报告和 直接评估将提供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等位基因引起的儿童期不良发育。

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.