Genomic Disorders and Cognitive Development

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.

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.