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

2010年，英国有近120万智障人士，其中29.8万为18岁以下儿童。虽然智力残疾的原因可能是极端早产、出生损伤或脑部感染等事件，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(CNV)。最严重的CNV并不存在于父母双方身上，而是“新近发生”。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，检查患者DNA中CNV的成本正在大幅下降。如今，在英国，几乎所有向儿科服务机构出示身份证的儿童都要进行这项测试。英国国家医疗服务体系(NHS)支付费用，报告存储在英国区域遗传学中心(RGC)。在大约14%的人中，测试显示CNV可能是导致ID的原因。到2015年，每年将有多达4.5万人接受这些测试。因此，英国研资局拥有大量关于CNV的信息。在世界各地，人们对导致ID(以及相关疾病，如自闭症或癫痫)的遗传异常非常感兴趣。知道一种特定的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。我们不知道这些与基因异常有什么关系。在成年生活中，一些患有智障的人会患上更严重的精神疾病，如精神分裂症。我们不知道为什么这种疾病在一些ID患者中发生，而在另一些人中没有。当发现具有临床意义的CNV时，应该告诉家庭该儿童的未来是什么，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不足。我们的主要目标是创建一个新颖和全面的遗传知识库，与有关儿童和成年适应的详细信息相联系，我们将从两个研究阶段汇编这些知识。我们的Imagine遗留数据库将向管理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儿童和成人受益。在第一阶段，我们将利用基于NHS的CNV Reports资源提供的机会。由于每个具有临床意义的CNV都是罕见的，我们将不得不从所有英国RGC收集非常大的样本。我们将重点关注儿童早期到中期的行为调整，目标是招募大约10,000个家庭。我们将在网上或通过电话，使用经过充分测试的行为适应、社会环境和病史测量方法，获得关于这批儿童的行为和能力的家长报告。我们将在两年内对家庭进行跟踪，使我们能够评估情绪/行为问题的稳定性，确定环境风险的重要性，如父母心理健康、种族或贫困。在第二阶段，我们将重点关注4个相对常见的CNV，成年后心理健康不良的风险相对较高。我们的目标是通过深入的调查和个人评估，发现更多的风险和弹性影响。我们将从国家研究中选择有指定CNV的儿童，通过家庭评估来研究他们的能力和适应情况，并对他们进行2年以上的随访。我们还将招募具有相同4个CNV的ID成人，以研究长期结果。他们还将在家中接受访问和测试。通过这种方式，我们的目标是首次发现与这些重要的CNV有关的风险如何在儿童和成人中表现出来，并潜在地确定改善这种风险的干预点

In 2010, there were nearly 1.2 million people with intellectual disabilities (ID) in England, of whom 298,000 were children under 18 years of age. Although the cause of intellectual disability can be events such as extreme prematurity, birth injury 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 nowadays, 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 about 14%, the test reveals a CNV that is probably the cause of ID. Up to 45,000 people each year will have these tests by 2015. Consequently, there is an enormous wealth of information about CNV held within UK RGC. Around the world, there is great interest in the genetic anomalies that cause ID (and related conditions such as autism or epilepsy). Knowing that a particular CNV may cause ID is valuable, but ID is commonly associated with severe behavioural and emotional problems too. We do not know how these relate to the genetic anomaly. In adult life, some individuals with ID go on to have more serious mental illness such as schizophrenia. We do not know why this illness develops 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 linked to detailed information about adjustment in childhood and adulthood, which we will compile from the two study phases. Our IMAGINE legacy database will be accessible to clinicians managing people with ID, not only in the UK but also around the world, and its establishment will benefit ID children and adults alike.In the first phase, we will draw on the opportunity offered by the NHS-based resource of CNV reports. Because each clinically significant CNV is rare, we will have to collect a very large sample, from all UK RGC. We will focus on behavioural adjustment in early to middle childhood, and aim to recruit around 10,000 families. We will obtain parent reports about behaviour and abilities of this sample of children online, or by telephone, using well-tested measures of behavioural adjustment, social circumstances and medical history. We will follow-up families over 2 years to allow us to assess the stability of emotional/behavioural problems, to identify the importance of environmental risks, such as parental mental health, ethnicity or poverty. In the second phase, we will focus on 4 relatively common CNV with a relatively high risk of poor mental health in adulthood. Our aim is to discover, by intensive investigation and personal assessment, additional risk and resilience influences. We will select children with the designated CNVs from the national study, study their abilities and their adjustment by home-based assessments, and follow them up over 2 years. We will also recruit adults with ID who possess the same 4 CNVs, to study long-term outcomes. They will also be visited and tested at home. 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