Every year, up to 45,000 people in the UK learn that a rare genetic glitch—a copy number variation (CNV)—is the likely cause of their child’s intellectual disability, but no one can tell them what that means for the child’s future mental health. This matters because intellectual disability is often accompanied by severe behavioural problems and, in adulthood, serious mental illness like schizophrenia. Clinicians currently have no way to predict which children will develop these additional problems, or how to intervene early. The IMAGINE project aims to fill that gap by linking detailed genetic information from NHS records with long-term data on how children and adults actually fare. If successful, the research will create a comprehensive genetic knowledge base accessible to clinicians worldwide. Families could receive evidence-based guidance on managing behavioural and educational challenges to prevent poor mental health outcomes. For the first time, a positive genetic test result would come with a roadmap, not just a diagnosis.
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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.
Andre Strydom (Co-Investigator)David Skuse (Principal Investigator)Frances Raymond (Co-Investigator)Jeremy Hall (Co-Investigator)Marianne Van Den Bree (Co-Investigator)Michael Kerr (Co-Investigator)Michael Owen (Co-Investigator)Spiros Denaxas (Co-Investigator)Sylvia Richardson (Co-Investigator)William Mandy (Co-Investigator)
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