Genomic Disorders and Cognitive Development

Lead Research Organisation: University of Cambridge
Department Name: UNLISTED

Abstract

About 1 in 100 people worldwide has intellectual disability (ID), meaning that they have significant lifelong difficulties with learning, communication and independent living skills. ID often occurs alongside other physical and mental health difficulties, meaning that people with ID require high levels of support and often have poor quality of life. Currently the support that can be provided is mainly reactive and symptom-focused - tackling problems as and when they arise. This is because, until recently, we did not know the cause of ID for the majority of people, so it was not possible to predict problems at an earlier stage and provide more effective support tailored to the cause of each person’s condition.
This situation is now changing fast. New genetic testing technologies mean that it is possible to identify a specific cause in more than half of people with ID. Testing is available within the NHS, and in many global health settings. Genetic diagnosis provides new opportunities to understand each person’s ID, and use this knowledge to improve physical and mental health. To achieve this, our research aims to bridge the gaps between the molecular cause of ID and the lifelong cognitive and mental health difficulties experienced by each person.

Technical Summary

The goal of this programme is to integrate genomic medicine with cognitive neuroscience to improve our understanding of neurodevelopmental disorders, and change long-term mental health outcomes for affected individuals and their families. Toward this goal, our objectives are (1) to map the neurodevelopmental correlates of genomic variation, (2) to discover the cognitive and neural mechanisms linking genomic variation to symptoms and impairments, and (3) to investigate how genomic disorders interact with social context to influence well-being.
Each genomic disorder is extremely rare – our strategy is to investigate groups of genomic disorders defined by convergent impact on physiological processes (gene functional networks). One gene functional network which is a particular focus of the programme is synaptic vesicle cycling disorders, including Synaptotagmin 1-associated and STXBP1-associated neurodevelopmental disorders. Other current projects focus on chromatinopathy disorders and Wnt-signalling disorders.

Clinical presentations of genomic disorders within each functional network are complex and variable between individuals and within individuals over time. To understand this variability, we apply a transdiagnostic framework to investigate dimensional impairments and underlying cognitive and neural systems. To achieve this we use a variety of human cognitive neuroscience methods – behavioural questionnaires, interviews and structured observations; standardised neuropsychological assessments; bespoke cognitive tests; structural and functional neuroimaging via MRI; neurophysiology via MEG and EEG. We also analyse big datasets enabling larger-scale analyses of genotype-phenotype relationships.

We engage in interdisciplinary collaborations with functional biologists to link molecular and cellular mechanisms to patients’ neurobiology and symptoms. To achieve clinical relevance we integrate social and biological understanding of mental health - we work closely with psychologists to connect neurobiology and cognition to lived experience and relationships.

Our translational goal is to develop 4P (participatory, personalised, predictive, preventive) medicine strategies that will improve mental health and quality of life for individuals with neurodevelopmental genomic disorders and their families.

People

ORCID iD

Related Projects

Project Reference Relationship Related To Start End Award Value
MC_UU_00030/1 01/04/2022 31/03/2027 £2,366,000
MC_UU_00030/2 Transfer MC_UU_00030/1 01/04/2022 31/03/2027 £2,141,000
MC_UU_00030/3 Transfer MC_UU_00030/2 01/04/2022 31/03/2027 £1,964,000
MC_UU_00030/4 Transfer MC_UU_00030/3 01/04/2022 31/03/2027 £2,535,000
MC_UU_00030/5 Transfer MC_UU_00030/4 01/04/2022 31/03/2027 £2,771,000
MC_UU_00030/6 Transfer MC_UU_00030/5 01/04/2022 31/03/2027 £2,242,000
MC_UU_00030/7 Transfer MC_UU_00030/6 01/04/2022 31/03/2027 £1,219,000
MC_UU_00030/8 Transfer MC_UU_00030/7 01/04/2022 31/03/2027 £2,464,000
MC_UU_00030/9 Transfer MC_UU_00030/8 01/04/2022 31/03/2027 £2,753,000
MC_UU_00030/10 Transfer MC_UU_00030/9 01/04/2022 31/03/2027 £1,898,000
MC_UU_00030/11 Transfer MC_UU_00030/10 01/04/2022 31/03/2027 £2,148,000
MC_UU_00030/12 Transfer MC_UU_00030/11 15/10/2021 31/03/2027 £1,375,000
MC_UU_00030/13 Transfer MC_UU_00030/12 01/11/2021 31/03/2027 £1,261,000
MC_UU_00030/14 Transfer MC_UU_00030/13 01/04/2022 31/03/2027 £1,238,000
MC_UU_00030/15 Transfer MC_UU_00030/14 01/04/2022 31/03/2027 £2,102,000
 
Description Access to Expertise, within Translational Partnership Award, administered by Cambridge Academy of Therapeutic Science
Amount £14,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2022 
End 09/2023
 
Description Cambridge Biomedical Research Centre integrative genomics theme
Amount £160,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 10/2022 
End 09/2027
 
Description Cambridge Biomedical Research Centre mental health theme
Amount £14,740 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 10/2022 
End 09/2027
 
Description 100,000 Genomes Project 
Organisation Genomics England
Country United Kingdom 
Sector Public 
PI Contribution Via membership of the Neurology GECip, our programme has conducted two analyses of 100K data. Analyses were carried out by two MPhil in Genomic MEdicine students, both of whom obtained distinctions for their work within this collaboration. Both projects are currently being written up for publication.
Collaborator Contribution Genomics England generated the hugely valuable Rare Disorders cohort, with whole genome sequencing and HPO annotations.
Impact MPhil thesis: Analysis of Human Phenotype Ontology (HPO) Terminologies in Synaptic Vesicle Cycling (SVC) Disorders. Sokanha Kong. Multidisciplinary - genomic medicine, clinical neuroscience. MPhil thesis: The Genomics of Cerebral Visual Impairment. Emogene Shaw. Multidisciplinary - genomic medicine, ophthalmology, clinical neuroscience.
Start Year 2020
 
Description COIN project 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am co-investigator on a project led by Charlotte Tye to investigate the impact of the COVID19 impact on individuals with rare neurogenetic disorders and their families. Funded by a project grant from Baily Thomas Charitable Trust
Collaborator Contribution Involvement in project design, funding applications, methods development, data analysis and outputs.
Impact none to date
Start Year 2020
 
Description Decipher and DDD 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Phenotyping investigations of patients diagnosed within the DDD project Analysis of Decipher cohort phenotyping data
Collaborator Contribution Anonymised patient phenotyping and genomic data
Impact STXBP1 complementary analysis project - Suri et al 2017 STXBP1 phenotyping paper in preparation
Start Year 2013
 
Description IMAGINE parents 
Organisation IMAGINE ID
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Collaborative access to IMAGINE dataset. Concepts, study design, data analysis, manuscript preparation
Collaborator Contribution Conceptual and statistical expertise, manuscript preparation
Impact Paper in preparation
Start Year 2018
 
Description IMAGINE parents 
Organisation University of Birmingham
Department School of Psychology Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative access to IMAGINE dataset. Concepts, study design, data analysis, manuscript preparation
Collaborator Contribution Conceptual and statistical expertise, manuscript preparation
Impact Paper in preparation
Start Year 2018
 
Description IMAGINE parents 
Organisation University of Cambridge
Department Centre for Family Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative access to IMAGINE dataset. Concepts, study design, data analysis, manuscript preparation
Collaborator Contribution Conceptual and statistical expertise, manuscript preparation
Impact Paper in preparation
Start Year 2018
 
Description Sarah Gordon SVC physiology Florey Institute 
Organisation Florey Institute of Neuroscience and Mental Health
Country Australia 
Sector Academic/University 
PI Contribution We contribute clinical phenotyping and genomic variant information. Gordon and team carry out in vitro functional studies. We integrate this information to characterise the SVC disorders spectrum and discover mechanisms contributing to symptoms and symptom variation. Now funded via Sparks/GOSH award (PI Baker, Co-Pi Gordon) and NHMRC award (PI Gordon, co-PI Baker)
Collaborator Contribution Functional studies of SVC neurodevelopmental disorder variants
Impact Baker, Gordon et al JCI (2015) Baker, Gordon et al Brain (2018)
Start Year 2013
 
Description Synapse Centre 
Organisation East Suffolk and North Essex NHS Foundation Trust
Country United Kingdom 
Sector Hospitals 
PI Contribution I have contributed to discussions about the goals and discussions about this new centre. I have delivered a lecture to the Centre. I have submitted one funding application connected to the Centre, and intend to develop further links and concrete project proposals over the next year.
Collaborator Contribution The collaboration is led by Dr Ben Marlow and colleagues, who have spearheaded a vision for a translational research centre for East of England.
Impact Interdisciplinary research, linked to a multidisciplinary neurodisability service.
Start Year 2020
 
Description Cambridge Neuroscience Interdisciplinary Seminar - SVC disorders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Around 20 investigators and clinicians from across diverse Cambridge departments attended an online talk about SVC disorders. This stimulated new collaborations.
Year(s) Of Engagement Activity 2022
URL https://youtu.be/TcDw4L4ysGA
 
Description ERUK Shape Network live 
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 I contributed a lecture to an ERUK research training day for the SHAPE network. This included people with epilepsy and carers, who act as an advisory group for the funder.
Year(s) Of Engagement Activity 2022
URL https://www.youtube.com/watch?v=Dpo87f7QaBI
 
Description Rare Disease family day at Sanger 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Family day for participants on the Next Generation Children's project and other local families affected by rare disease
Year(s) Of Engagement Activity 2022