IMAGINE-2: Stratifying Genomic Causes of Intellectual Disability by Mental Health Outcomes in Childhood and Adolescence

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

In England, there are over a million people with learning disabilities, a quarter of whom are children of school age. Most moderate to severe intellectual disability (ID) has a genetic cause. In order to identify those genetic risks, the NHS is now routinely screening the DNA of children who have significant developmental delays. Being informed that their child's ID is caused by a genetic change is of value to parents. But, at present, we can rarely use that information to advise on best management of behavioural and educational issues, or to reduce the risk of poor mental health outcomes. Our study aims to fill that gap in knowledge.

Our IMAGINE-ID programme of research began in 2014. By 2019 we had recruited nearly 3500 UK families whose child has ID due to a genetic cause. Using a combination of online interviews, questionnaires, and face-to-face meetings with families, we built up a comprehensive picture of those children's strengths and weaknesses. We discovered there was a far greater risk of severe behavioural and emotional problems than was previously recognised. Whilst children with ID from the general population are about six times as likely to have problems of this nature, the risk is over thirty times greater if the disability has a genetic cause.

We also discovered that children whose genetic risk was inherited had more severe emotional and behavioural problems than those in which the equivalent change occurred by chance. Perhaps parents who carry the genetic anomaly could be mildly affected by it, although they do not share the same degree of disability as their child? They are more likely than other families participating in our research programme to live in disadvantaged circumstances with overcrowding, poor quality housing, and unemployment. Adverse social circumstances would contribute to parenting difficulties and exacerbate their child's problems. We need to learn more about these important points of vulnerability. Families at risk could be identified sooner, and supported more effectively in future, if we understood more about the processes that led to their difficulties. These questions will be addressed by our new research.

We will follow up and interview all participants 5 years after our initial assessment, to ask: first, have the mental health issues we uncovered in the previous study persisted? Second, if they have persisted, or improved, what are the medical, educational and environmental factors that have changed since we first met those families?

Most children we saw in the first study were between 6 and 13 years of age. During our follow-up, many will be entering adolescence or early adulthood. That is a time when the risks of some mental health problems become substantially greater. We will be endeavouring to discover whether the young person's behavioural and emotional adjustment, or their risk of emerging mental health disorders, is influenced by the educational, medical or other support their families have received over the past 5 years. We will be looking for clues that pinpoint those children with the best and worst outcomes.

More than one in three children in IMAGINE-ID had an Autism Spectrum Disorder. A quarter had ADHD, and a similar proportion had either severe anxiety or serious challenging behaviour. What was the impact on those children's educational progress? To what extent were those conditions recognised and treated by their local medical and mental health services? To gather that information, we will supplement what we learn from parents in the course of our follow-up interviews with nationally collected records on the children's education (from the National Pupil Database) and on their medical history (from the NHS Hospital Episode Statistics Database). We will also use information from medical records to learn more about the strong association between ID with a genetic cause and seizures, which affect up to 70% of children in the IMAGINE-ID cohort

Technical Summary

Our genotype-first study IMAGINE-ID recruited 3402 children from UK NHS Regional Genetics Clinics, whose intellectual disability (ID) is associated with either a pathogenic Copy Number Variant (CNV-75.9%) or Single Nucleotide Variant (SNV-23.6%) or both (0.5%). 84% of consented families provided standardized assessments of their child's mental health, functional adaptation, medical and educational history, and family/social environment. We have data on 4,054 genetic variants, logged for 3,398 individuals, representing 3,117 CNVs (1,534 in recognised syndromes, 1,583 unique) and 944 SNVs in 278 different genes. 57% of IMAGINE-ID participants had one or more psychiatric diagnoses: Autism Spectrum Disorders (38%); ADHD (24%); anxiety disorders (12%); challenging behaviour (13%). 31% had a history of seizures, 57% take anticonvulsant medication. Little specificity was found between genotype and diagnostic phenotype, implying multiple developmental processes lead to broadly similar outcomes. Defining potential subtypes of complex neurodevelopmental disease, based on genetic risk, will be facilitated by the observation of longitudinal trajectories of neurodevelopment into adolescence and early adulthood. We aim to conduct a 5-year longitudinal study of the cohort with annual on-line phenotyping of all participants, supplemented by intensive face-to-face assessments of over 500 young people with highly pathogenic CNV that were intensively studied in our first phase. We have already found that environmental risk factors are key to child adjustment, potentially accounting for the majority of variance in outcomes. In our intensive family study, we will test hypotheses about potential mediating variables: for instance, we know children with an inherited CNV are at greater risk, indicating the importance of family environment. We will measure the role of educational and medical support by linkage to the National Pupil Database and NHS Digital's Hospital Episode Statistics.

Planned Impact

The short-term impact is 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 liaise with stakeholders, including parent-support organizations, and hold focus groups/conferences at which potential benefits are discussed.

In the UK, specialist genetic investigations for children with ID rarely translate into specific recommendations for behavioural management or prognostic statements about mental health outcomes. Our PPI has shown families would strongly welcome such knowledge. By linking genotypic data on specified SNV/CNV with standardized phenotypic data, our study has generated clinically valuable information. Unusual behaviour patterns or emotional disorders associated with ID are often ascribed to poor parenting practices. Recognising common disorder-specific patterns is the first step to reassuring parents, and educating clinicians/social support staff. Impact will reduce self-blaming and stress, with resultant improved quality of life for affected families. Impact timescale < 5 years.

Child behaviour can be reliably and easily measured across time, and may independently predict future symptoms and psychiatric disorders, including the process by which disturbed emotions and behaviour can undermine family/individual quality of life. Our findings already indicate opportunities for intervention. We aim to enhance parent and child wellbeing (e.g. by promoting their mental health, reducing school exclusions, limiting risk of parental separation), which may have a beneficial economic impact. Impact timescale <5 years.

Education and Care Professionals:
Intellectual disability implies global impairments in cognitive skills and functional adaptation. Nevertheless, some developmental trajectories may be preserved. We aim to parse the wide range of ID syndromes by CNV/SNV subtyping. Stratification may allow the identification of rare variant disorders in which islets of ability are preserved. Gaining such knowledge about specific CNV/SNV has implications for education planning, and fostering the maximisation of individual potential. Such discoveries, supplemented by data retrieved from the National Pupil Database and Hospital Episode Statistics could inform policy on management. Information on environmental factors influencing, for instance, the emergence of challenging behaviour (when linked to specific genotypic risks) could point to the value of early interventions, thus reducing risk of transfer to residential care and the associated costs. Impact timescale <5 years.

Clinical Pharmacology Developmental pathways:
Neurodevelopmental risk encompasses (inter alia) autism, schizophrenia, and epilepsy. We lack a lifespan perspective on risk related to genotype. In our accelerated longitudinal cohort study, linking genotype to phenotype could lead to pathway and network analysis of complex 'omics data on the basis of identified genotypes. Potential collaborations could lead, in longer term, to academic-pharmaceutical industry partnerships and 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 have fostered the academic skills of junior staff, several of whom have already obtained PhD Fellowships (Wellcome/NIHR). Impact timescale <5 years.

International collaborations:
We have established the foundations of international partnerships with The Centre for Applied Genomics (Univ. Toronto), The Autism and Developmental Medicine Institute (Geisinger Health System, Lewisburg), The Simons Simplex Collection Global Consortium, among others (see appended letters of support). Impact timescale:<5 years.

Publications

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Baker K (2021) Childhood intellectual disability and parents' mental health: integrating social, psychological and genetic influences. in The British journal of psychiatry : the journal of mental science

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Chawner SJ (2021) Clinical evaluation of patients with a neuropsychiatric risk copy number variant. in Current opinion in genetics & development

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Chawner SJRA (2022) Autism: A model of neurodevelopmental diversity informed by genomics. in Frontiers in psychiatry

 
Title Share your Rare 
Description In collaboration with Phenotypica, creative workshops were carried out with the rare genetic condition community to produce poetry and artwork. https://www.ncmh.info/engagement-involvement/creative-complexity/ 
Type Of Art Artwork 
Year Produced 2022 
Impact Opened up conversations on genomics and mental health. Developed stronger links with third sector organisations, including Genetic Alliance UK. 
URL https://phenotypica.org/projects/share_your_rare/index.html
 
Description Child of the North 2024 Campaign
Geographic Reach National 
Policy Influence Type Citation in other policy documents
URL https://www.n8research.org.uk/research-focus/child-of-the-north/2024-campaign/
 
Description Department of Health and Social Care workshop on access to mental health services in children and young people with rare conditions
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
 
Description Expert steering group to support an NIHR & DHSC evidence synthesis on rare conditions and mental health
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
 
Description IMAGINE publication citation in report prepared for the Child of the North All-Party Parliamentary Group
Geographic Reach National 
Policy Influence Type Citation in other policy documents
Impact The Child of the North APPG have circulated the repot widely and aim to use the report to develop policy solutions that will create lasting change.
URL https://www.healthequitynorth.co.uk/app/uploads/APPG-REPORT-SEPT-23.pdf
 
Description Multi stakeholder workshop on genomics in education
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
 
Description Organised workshop in collaboration with the Government's Department of Health and Social Care (DHSC) on the topic of accessing mental health services for children and young people living with rare conditions.
Geographic Reach National 
Policy Influence Type Citation in other policy documents
 
Description EATING DISORDERS AND SELF-HARM FELLOWSHIP
Amount £289,575 (GBP)
Funding ID MRF-058-0015-F-CHAW-C0867 
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 09/2021 
End 09/2024
 
Description The impact of schizophrenia-associated copy number variants on cortical network dynamics
Amount £2,002,079 (GBP)
Funding ID MR/W028395/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2022 
End 04/2027
 
Description The relationship between the 16p11.2 locus and eating disorders: Novel insights from rare genetic conditions
Amount £289,575 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 09/2024
 
Description mental health Seed Fund
Amount £6,918 (GBP)
Organisation The Child Health Research Charitable Incorporated Organisation 
Sector Academic/University
Country United Kingdom
Start 02/2023 
End 12/2023
 
Description Genes 2 Mental Health Network (G2MH) 
Organisation National Institutes of Health (NIH)
Department National Institute of Mental Health (NIMH)
Country United States 
Sector Public 
PI Contribution Increased awareness of the rick of physical and mental health multimorbidity in people with Copy Number Variation.
Collaborator Contribution Opportunities for collaboration with a large NIMH-led network of international researchers studying rare genetic variation and mental health. The G2MH network also offers opportunities for replication of our findings in a large international data set.
Impact As above
Start Year 2019
 
Description "Share your rare" live sci-art installation at Subatomic Circus as part of Cardiff Science Festival and Cardiff Council's Summer of Smiles 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Engage children in science and art as part of Cardiff Council's "Summer of Science", to provide educational enrichment following lockdown
Year(s) Of Engagement Activity 2021
URL https://www.cardiff.ac.uk/news/view/2541105-share-your-rare-rare-genetic-conditions-and-mental-healt...
 
Description ACAMH podcast 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I recorded a Papers Podcast, focused on my JCPP Advances paper 'Neurodevelopmental dimensional assessment of young children at high genomic risk of neuropsychiatric conditions' (https://doi.org/10.1002/jcv2.12162).

Discussion points included:

What are copy-number variants (CNVs) and how they impact child development.

Insight into what 22q11.2 deletion syndrome is, how it is typically diagnosed, and how it is associated with psychiatric risk.

Implications for clinicians and CAMH professionals.

Whether there are adequate interventions targeted at early age groups.

Recommendations for prevention, detection, and the targeting of interventions.
Year(s) Of Engagement Activity 2023
URL https://www.acamh.org/podcasts/neurodevelopmental-genomic-risk-neuropsychiatric-conditions/
 
Description All Wales Medical Genomics Service 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact I presented the outcomes of research on copy number variants to clinical staff at Cardiff University Hospital's All Wales Medical Genomics Service. This sparked questions and discussion, and increased knowledge of psychiatric risk CNVs amongst clinicians.
Year(s) Of Engagement Activity 2022
 
Description Department of Medical Genetics, Oslo University Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I presented the outcomes of research on copy number variants to clinical staff at Oslo University Department of Medicial Genetics. This sparked questions and discussion, and increased knowledge of psychiatric risk CNVs amongst clinicians.
Year(s) Of Engagement Activity 2022
 
Description Developmental Theme Meeting: The impact of rare copy number variants on childhood development 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact A presentation of findings from IMAGINE-1 to researchers across the National Mental Health Research Institute and the Dementia Research Institute at Cardiff University, as an opportunity to discuss findings and raise awareness of the research to researchers in similar fields.
Year(s) Of Engagement Activity 2021
 
Description Eating Disorder Psychiatric Genetics Consortium seminar series "The relationship between the 16p11.2 locus and eating disorders: novel insights from rare genetic conditions" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Raising awareness of rare genetic conditions to eating disorder clinicians and researchers
Year(s) Of Engagement Activity 2021
 
Description Emerging Minds Research and Patient summit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Workshop on engaging children and young people in mental health research

Eva Sprecher, Jackie Parsonage-Harrison, Kimberley Peterson, Vilas Sawrikar, Buket Kara, Eleanor Chatburn, Josefien Breedvelt, Jeanne Wolstencroft, Ola Demkowicz, and Hannah White from the GROW Early Career Researcher Development Programme Cohort. Workshop: Meeting of minds: imagining the future of children and young people's mental health research. The Big Emerging Minds Summit, 17th October 2022
https://emergingminds.org.uk/workshop-meeting-of-minds-imagining-the-future-of-children-and-young-peoples-mental-health-research/
Year(s) Of Engagement Activity 2022
URL https://emergingminds.org.uk/workshop-meeting-of-minds-imagining-the-future-of-children-and-young-pe...
 
Description Genetic Alliance Community Chat 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Third sector organisations
Results and Impact Presented Imagine ID study findings to Genetic Alliance Community members and charities.
Year(s) Of Engagement Activity 2022
 
Description Genetic Alliance Genomics cafe " Share Your Rare: a creative project exploring the experience of living with a rare condition" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Raising awareness of rare genetic conditions and research
Year(s) Of Engagement Activity 2022
 
Description IMAGINE participant study engagement group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Study participants or study members
Results and Impact Imagine participant study consultation group, regularly attended by 20 individuals. The lively discussion directly informs the study processes.
Year(s) Of Engagement Activity 2020,2021,2022
 
Description IMAGINE-ID Longitudinal Study: Mental health and behaviour in a National Cohort of UK Children with Intellectual Disability of genetic aetiology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk at international conference: Society for Study of Behavioural Phenotypes:

Wolstencroft, J., IMAGINE ID & Skuse. IMAGINE-ID Longitudinal Study: Mental health and behaviour in a National Cohort of UK Children with Intellectual Disability of genetic aetiology. Society for the Study of Behavioural Phenotypes, September 2022, Oslo, Norway
Year(s) Of Engagement Activity 2022
 
Description Imagine ID data used by Genetic Alliance in response to DHSC consultation on the Downs Syndrome Act 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Collaborated with Genetic Alliance UK to write response to DHSC consultation on the Downs Syndrome Act using the IMAGINE-ID study data.
Year(s) Of Engagement Activity 2022
 
Description Invited 22q11 Europe presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact I was invited to present on behalf of the IMAGINE-ID study a talk on sleep and mental health in 22q11.2 Deletion Syndrome, at the European 22q11 caregiver conference in Dublin. The talk led to questions from caregivers afterwards about the research, and strengthened links with third sector charitable organisations including 22q11 Ireland and MaxAppeal (UK 22q11 charity).
Year(s) Of Engagement Activity 2023
URL https://22q11europe.org/
 
Description Invited keynote speaker by Cheshire and Wirral Partnership NHS Foundation Trust 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact I was invited by Cheshire & Wirral NHS to present at their Centre for Autism, Neuro-Developmental Disorders, and Intellectual Disability conference, providing an opportunity to disseminate research findings on rare genetic conditions to clinicians and other stakeholders.
Year(s) Of Engagement Activity 2024
URL https://www.canddid.nhs.uk/conf24
 
Description Invited presentation on future of research into rare genomic variants. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation at the Future MINDDS: Recent advances and future directions for research of Neurodevelopmental Disorders (NDD) associated with pathogenic CNV (Copy Number Variants), conference, EU COST action-funded, Cardiff.
Year(s) Of Engagement Activity 2022
 
Description Invited speaker at the South West of Britain NHS medical genomics meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact I was an invited speaker for a conference event for regional medical genomic services held at Cardiff Heath Hospital. I was invited to present findings from the IMAGINE-ID study and on 16p11.2 genetic conditions.
Year(s) Of Engagement Activity 2023
 
Description Invited talk at Frambu 16p11.2 caregiver workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I was invited by Frambu Centre for Rare Disease in Norway to present at their national gathering for 16p11.2 Duplication Syndrome, covering the latest research for parents and caregivers.
Year(s) Of Engagement Activity 2023
URL https://frambu.no/kurs/16p11-2-duplikasjon/
 
Description MINDDS training school "Eating problems and eating disorders in neuropsychiatric risk CNV carriers" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Promoting research on eating disorders and rare genetic conditions to the european psychiatric genetic researchers and clinicians.
Sharing of research assessment protocols
Year(s) Of Engagement Activity 2022
 
Description Media piece 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Charity Cerebra reports on our research February Newsflash: Making waves with the BBC! (cerebra.org.uk).
Year(s) Of Engagement Activity 2023
URL https://cerebra.org.uk/?mailpoet_router&endpoint=view_in_browser&action=view&data=WzE0OSwiNDYzMWU1MT...
 
Description Presentation about neurodevelopmental conditions in young people with rare genetic deletions or duplications 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation given at the NEURODEV conference. Neurodevelopmental disorders: from molecular mechanisms to social inclusion. 7th Bordeaux Neurocampus Conference, Bordeaux University, Bordeaux, France.
Year(s) Of Engagement Activity 2022
URL https://brainconf.u-bordeaux.fr/en/Former-conferences/NeuroDev-May-2022/r1228.html
 
Description Presentation to Bristol Cleft Collective 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation about our research findings of the phenotypic features associated with having a rare chromosomal deletion or duplication (as Copy Number Variant).
Year(s) Of Engagement Activity 2023
 
Description World Congress of Psychiatric Genetics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Share research findings of the IMAGINE-ID study
Year(s) Of Engagement Activity 2021