Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE)

2013年，英国有110万智障人士（ID）；224,930人是学龄儿童。虽然这种残疾的原因可能是极端早产或脑部感染等事件，但遗传因素可能占85%。有些遗传风险是遗传的，但不是全部。最近的研究表明，在卵子或精子的形成过程中，可能会发生轻微的染色体结构异常。它们被称为拷贝数变异（CNVs）。最严重的变异不存在于双亲中，而是“新出现的”。幸运的是，这些都是罕见的事件，但如果它们发生在我们基因组的关键区域，它们与ID密切相关。如今，检测患者DNA CNV的成本正在大幅下降。在英国，几乎所有到儿科就诊的儿童都要做这个测试。国家卫生服务体系（NHS）支付费用，报告保存在英国区域遗传中心（RGC）。在10-15%的情况下，测试显示CNV可能是导致ID的原因。每年有多达45000人接受这些检查。因此，在英国RGC内部有大量关于CNV的信息。知道特定的CNV可能导致ID是有价值的，但ID通常也与严重的行为和情感问题有关。成年后，许多本我患者会患上更严重的精神疾病，比如精神分裂症。我们目前还不明白为什么这些问题出现在一些ID患者身上，而其他人却没有。当在患有ID的孩子身上发现临床意义重大的CNV时，家庭应该被告知孩子的未来，以及他们应该如何最好地管理行为和教育问题，以避免不良的心理健康结果。我们独特而新颖的研究计划旨在纠正这一缺陷。我们的主要目标是创建一个新的和全面的遗传知识库，包括广泛的罕见的CNV，与遗传异常对儿童和成年期适应的影响的详细信息相关联。在过去的一年里，我们一直在测试mrc资助的研究策略的可行性，并实现了我们所有的目标。我们现在正着手进行一项为期三年半的研究计划，以建立我们已经建立的基础设施。我们的IMAGINE遗产资源将对管理ID患者的临床医生开放，不仅在英国，而且在世界各地，它的建立将使ID患者及其家人在整个生命周期中受益。在一个工作流程中，我们正在利用基于国民保健制度的CNV报告资源提供的机会。我们将重点关注儿童的行为调整，目标是在全国招募约5000个家庭。我们已经证明，通过使用行为调整、社会环境和病史等久经考验的措施，可以在网上或通过电话获得家长关于儿童行为和能力的报告。家长们都很热情地向我们介绍他们的孩子，他们很重视我们在完成在线评估后发给他们的报告。这些为学校和临床医生提供了有用的总结。在另一个工作流程中，重点是一些相对常见的CNV，它们与成年后心理健康状况不佳的风险特别高有关。我们从国家研究中选择具有指定cnv的儿童，通过家庭评估来研究他们的能力和适应能力。我们将评估情绪和行为问题的严重程度，以及环境风险的重要性，如父母的心理健康、种族或贫困。我们还将招募具有相同相对常见的CNVs的ID成年人来研究长期结果。通过这种方式，我们的目标是首次发现与这些重要的CNV相关的风险如何在儿童和成年期表现出来，并潜在地确定干预点以改善这种风险。

In 2013, there were 1.1 million people with intellectual disabilities (ID) in England; 224,930 were children of school age. Although the cause of such disability can be events such as extreme prematurity or brain infections, genetic factors could account for 85%. Some genetic risk is inherited, but not all. Recent research has shown that, during the formation of the egg or sperm, minor chromosomal structural anomalies can occur. They are known as copy number variations (CNVs). The most serious CNVs are not present in either parent, but are 'newly occurring'. Fortunately, these are rare events, but if they occur in key regions of our genome they are strongly associated with ID. Nowadays, the cost of examining a patient's DNA for CNV is coming down dramatically. In the UK nearly all children with ID presenting to paediatric services have the test. The National Health Service (NHS) pays, and reports are stored in the UK Regional Genetics Centres (RGC).In 10-15% the test reveals a CNV that is probably the cause of ID. Up to 45,000 people each year have these tests. Consequently, there is an enormous wealth of information about CNV held within UK RGC. Knowing that a particular CNV may cause ID is valuable, but ID is commonly associated with severe behavioural and emotional problems too. In adult life, many individuals with ID go on to have more serious mental illness, such as schizophrenia. We do not currently understand why these problems develop in some people with ID but not in others. When a clinically significant CNV is found in a child with ID, families deserve to be told what the future holds for that child, and how they should best manage behavioural and educational issues to avert poor mental health outcomes. Our unique and novel programme of research aims to rectify that deficiency. Our main objective is to create a novel and comprehensive genetic knowledge base, incorporating a wide range of rare CNV, linked to detailed information about the genetic anomaly's impact on adjustment in childhood and adulthood. We have spent the past year testing the feasibility of our MRC-funded research strategy, and have achieved all our objectives. We are now embarking on a further 3.5 year programme of research to build on the infrastructure we have created. Our IMAGINE legacy resource will be accessible to clinicians managing people with ID, not only in the UK but also around the world, and its establishment will benefit people with ID and their families throughout the lifespan. In one workstream, we are drawing on the opportunity offered by the NHS-based resource of CNV reports. We will focus on behavioural adjustment in childhood, and aim to recruit around 5,000 families nationally. We have shown that it is possible to obtain parent reports about behaviour and abilities of children online, or by telephone, using well-tested measures of behavioural adjustment, social circumstances and medical history. Families are enthusiastic to tell us about their children and they value the reports we send them, following completion of our online assessments. These provide a useful summary for schools and clinicians alike.In the other workstream, the focus is on a few relatively common CNV that are associated with a particularly high risk of poor mental health in adulthood. We select children with the designated CNVs from the national study, study their abilities and their adjustment by home-based assessments,. We will assess the severity of emotional and behavioural problems, and the importance of environmental risks, such as parental mental health, ethnicity or poverty. We will also recruit adults with ID who possess the same relatively common CNVs, to study long-term outcomes. In this way we aim to discover, for the first time, how the risk attaching to these important CNV manifests in childhood and adulthood, and potentially identify points for intervention to ameliorate that risk.