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

智力障碍和心理健康：评估基因组对神经发育的影响（IMAGINE）

• 批准号: MR/L011166/1
• 负责人: David Skuse
• 金额: $ 81.74万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL011166%2F1
• 关键词: Intellectual; Disability; Mental; Health; Assessing

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

2010年，英格兰有近120万智力残疾人，其中29.8万人是18岁以下的儿童。虽然智力残疾的原因可能是极端早产、产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（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。如今在英国，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）。在大约14%的情况下，测试显示CNV可能是ID的原因。到2015年，每年将有多达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。在世界各地，人们对导致ID（以及自闭症或癫痫等相关疾病）的遗传异常非常感兴趣。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。我们不知道这些与遗传异常有何关系。在成年生活中，一些患有ID的人继续患有更严重的精神疾病，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，与有关儿童和成年期适应的详细信息相关联，我们将从两个研究阶段中汇编这些信息。我们的IMAGINE遗留数据库将可供管理ID患者的临床医生访问，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NHS CNV报告资源提供的机会。因为每一个临床上显著的CNV是罕见的，我们将不得不收集一个非常大的样本，从所有英国RGC。我们将重点关注儿童早期至中期的行为调整，目标是招募约10，000个家庭。我们将在线或通过电话获得有关此样本儿童行为和能力的家长报告，使用经过充分测试的行为调整，社会环境和病史措施。我们将对这些家庭进行为期2年的随访，以评估情绪/行为问题的稳定性，确定环境风险的重要性，例如父母的心理健康，种族或贫困。在第二阶段，我们将重点关注4种相对常见的CNV，这些CNV在成年后心理健康状况较差的风险相对较高。我们的目标是通过深入调查和个人评估，发现额外的风险和弹性影响。我们将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，并随访2年以上。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这些重要的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

项目成果

Behavioural and neurodevelopmental characteristics of SYNGAP1

SYNGAP1 的行为和神经发育特征

• DOI: 10.21203/rs.3.rs-3722732/v1
• 发表时间: 2023
• 作者: Bednarczuk N

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.

• DOI: 10.1038/s41380-021-01182-2
• 发表时间: 2022-03
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Chapman, Gareth;Alsaqati, Mouhamed;Lunn, Sharna;Singh, Tanya;Linden, Stefanie C.;Linden, David E. J.;van den Bree, Marianne B. M.;Ziller, Mike;Owen, Michael J.;Hall, Jeremy;Harwood, Adrian J.;Syed, Yasir Ahmed
• 通讯作者: Syed, Yasir Ahmed

Sleep disturbance as a transdiagnostic marker of psychiatric risk in children with neurodevelopmental risk genetic conditions

睡眠障碍作为神经发育风险遗传性疾病儿童精神风险的跨诊断标志

• DOI: 10.21203/rs.3.rs-1922492/v1
• 发表时间: 2022
• 作者: Chawner S

Sleep disturbance as a transdiagnostic marker of psychiatric risk in children with neurodevelopmental risk genetic conditions.

• DOI: 10.1038/s41398-022-02296-z
• 发表时间: 2023-01-11
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Chawner, Samuel J. R. A.;Evans, Alexandra;Williams, Nigel J.;Owen, Michael;Hall, Jeremy;van den Bree, Marianne B. M.
• 通讯作者: van den Bree, Marianne B. M.

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome

使用诱导多能干细胞研究 1q21.1 缺失和重复综合征中的人类神经元表型

• DOI: 10.1101/2021.02.08.430246
• 发表时间: 2021
• 作者: Chapman G