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

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

Our study will evaluate the impact of rare CNV on risk of mental health disorder in childhood and adulthood by utilizing data on individuals with ID tested by aCGH within NHS UK genetics services (~100,000 by 01/04/2014). From data mining we will identify clinically significant CNV and conduct internet-based population phenotyping (~10,000 by 31/12/2016). We will take advantage of existing NHS resources and validated, inexpensive and appropriate methodologies for on-line phenotyping [80% of UK families have internet access at home]. The study offers remarkable value for money. It will comprise two primary workstreams (WS1 & WS2), which will be closely interconnected and complementary. First, a national phenotypic 'extensive' survey of children with ID who possess CNV abnormalities reported as clinically significant from (aCGH), based on data mining from UK Regional Genetics Centres (RGC). WS1 will focus on behavioural adjustment in early to middle childhood. Nearly all assessments will be on-line, or by telephone, using standardized measures of behavioural adjustment, social circumstances and medical history. Recruitment will continue from study years 2014-2016. A baseline assessment, with follow-up at 6, 12, 18 and 24 months (2016-2018) will allow evaluation of stability of emotional/behavioural problems in relation to genotype and will measure interacting factors linked to environmental risk. WS2 will conduct 'intensive' phenotyping of individuals with CNV-associated ID, focusing on 4 genetic anomalies previously reported to be associated with high risk of adverse mental health outcome and poor adaptive functioning [deletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2]. Children with the selected CNVs will be sourced from the national phenotypic study and followed up, initially over 24 months. Adults with ID carrying the same CNVs, sourced from UK NHS RGC, will be recruited to study long-term outcomes. Dedicated research teams will test participants in their homes.

Our study will impact short-term upon the domains of clinical practice and quality of life for affected families. Potential economic benefits include more efficient targeting of resources and reduced familial disruption. Longer-term, knowledge arising from genetic discoveries could support partnership with industry through targeted drug development. We will work closely with stakeholders throughout this programme, including the charity UNIQUE which will be represented on Scientific Advisory Board.

Clinicians
Clinicians increasingly request specialist genetic investigations for children with intellectual disability [ID] (35,000 tests p.a.). Usually, the results do not translate into specific recommendations for management or prognostic statements. By linking, for the first time, genotypic data on specified CNV with standardized phenotypic data, our study will generate clinically valuable information. Unusual behaviour patterns or emotional disorders are all too readily ascribed to inappropriate parenting practices, often by parents themselves. Recognizing common disorder-specific patterns is the first step to reassuring parents, and teaching clinicians/social support staff. Impact will reduce self-blaming and stress, with resultant improved quality of life for affected families. Impact timescale < 5years.

Children and Families affected by ID
Our follow-up studies will measure interaction cascades between genotypic/phenotypic characteristics of ID children and their influence upon family life, friendships, learning and leisure activities. Impact of child behaviour can be reliably and easily measured across time, and may independently predict future symptoms and psychiatric disorders. Potential value includes an opportunity to measure the interactive process by which disturbed emotions and behaviour can undermine family/individual quality of life. The approach should reveal new opportunities for intervention. Effective intervention can enhance parents' economic activity (e.g. by promoting their mental health, reducing school exclusions, limiting risk of parental separation). Impact timescale <5 years.

Education and Care Professionals
Intellectual disability implies global impairments in cognitive skills. Yet some developmental trajectories may be preserved (exemplified by the relatively good language skills of children with Williams syndrome). Parsing the wide range of ID by CNV subtyping, may allow the identification of rare variant disorders in which islets of ability are common. Gaining such knowledge about specific CNV has implications for education planning, and fostering the maximization of individual potential. Such discoveries could inform policy on the management of children with CNV-related ID, including support required to mainstream, or provision of speech and language services. Information on environmental factors influencing emergence of challenging behaviour linked to genotypic risk could point to genotype-specific interventions, reducing risk of transfer to residential care and the associated costs. Impact timescale <5 years.

Clinical Pharmacology
Developmental pathways in ID overlap with autism, schizophrenia, and epilepsy. We lack a lifespan perspective on risk related to genotype. Our accelerated longitudinal cohort study, linking genotype (with, in due course, supplementary genome-sequencing) to phenotype could facilitate pathway and network analysis of complex 'omics data in high-risk populations. There are potential synergies that could lead, in longer term, to academic-pharmaceutical industry partnerships leading to the discovery of causal mechanisms and potential novel drug targets for intervention. Impact timescale <10 years.

Training of skilled researchers
Within the framework of the program we will be fostering the academic skills of the three junior Co-I (Mandy, St Pourcain, Baker), all of whom are on a career track to senior positions. Impact timescale <5 years.