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

2013年，英格兰有110万智力残疾人，其中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大脑感染等事件，但遗传因素可能占85%。一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CNV不存在于任何父母，但“新出现”。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。在英国，几乎所有到儿科服务机构就诊的ID儿童都进行了测试。英国国家卫生服务体系（NHS）支付费用，报告存储在英国地区遗传学中心（RGC）。在10-15%的测试中，CNV可能是ID的原因。每年有多达45，000人进行这些测试。因此，英国研资局拥有大量关于CNV的信息。了解特定的CNV可能导致ID是有价值的，但ID通常也与严重的行为和情绪问题有关。在成年生活中，许多ID患者继续患有更严重的精神疾病，如精神分裂症。我们目前还不明白为什么这些问题在一些ID患者中发展，而在其他人中则没有。当在ID儿童中发现临床上显著的CNV时，家庭应该被告知该儿童的未来，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。我们独特和新颖的研究方案旨在纠正这一缺陷。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CNV，与有关遗传异常对儿童和成年期适应的影响的详细信息相关联。过去一年，我们一直在测试MRC资助的研究战略的可行性，并实现了我们的所有目标。我们现在正着手进行另一项为期3.5年的研究计划，以建立我们已经建立的基础设施。我们的IMAGINE遗产资源将提供给管理ID患者的临床医生，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NHS的CNV报告资源提供的机会。我们将侧重于儿童期的行为调整，目标是在全国招募约5 000个家庭。我们已经证明，可以通过在线或电话获得父母关于儿童行为和能力的报告，使用经过充分测试的行为调整措施，社会环境和病史。家庭都热情地告诉我们关于他们的孩子，他们重视我们发送给他们的报告，完成我们的在线评估后。在另一个工作流程中，重点是一些相对常见的CNV，这些CNV与成年后心理健康状况不佳的风险特别高有关。我们从全国研究中选择具有指定CNVs的儿童，通过家庭评估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性，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CNV的ID成人，以研究长期结果。通过这种方式，我们的目标是首次发现这些重要CNV的风险如何在儿童和成年期表现出来，并可能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.