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.
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.
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.
Organisations
- University of Cambridge (Lead Research Organisation)
- East Suffolk and North Essex NHS Foundation Trust (Collaboration)
- Florey Institute of Neuroscience and Mental Health (Collaboration)
- IMAGINE ID (Collaboration)
- UNIVERSITY OF BIRMINGHAM (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- Genomics England (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
People |
ORCID iD |
Kate Baker (Principal Investigator) |
Publications
Baker K
(2023)
Desert Island Papers.
in Brain and neuroscience advances
Brkic D
(2022)
[Formula: see text]FarmApp: a new assessment of cognitive control and memory for children and young people with neurodevelopmental difficulties.
in Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence
Chi Z
(2024)
Rare neurodevelopmental conditions and parents' mental health - how and when does genetic diagnosis matter?
in Orphanet Journal of Rare Diseases
Melland H
(2022)
Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder
in Genetics in Medicine
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 |