Title: Genomic Disorders and Cognitive Development
Funder: Medical Research Council

Abstract: Our technological ability to identify the cause of a developmental disorder is increasing at extraordinary pace. The success of large-scale NHS-based genomic cohort studies has led to major government commitment to mainstreaming diagnostics for developmental disorders. However, knowledge of phenotypes associated with each rare genetic disorder is lagging far behind. Levels of diagnostic uncertainty are currently high, and clinical utility of testing is not matching hopes of patients, families, clinicians and policy-makers. Unsurprisingly, there are few diagnosis-informed stratified approaches to promote developmental progress or reduce distressing symptoms. This new programme will apply best-available cognitive neuroscience approaches to characterise phenotypes and discover mechanisms in neurodevelopmental disorders of known genetic origin. The goals are to transform lifespan mental health for individuals with rare genetic disorders, and to elucidate neurodevelopmental systems contributing to mental health in the general population. The programme will apply a functional networks phenotyping approach to synaptic disorders i.e. disorders arising from high penetrance mutations to genes directly involved in synaptic structure, neurotransmission and plasticity. Synaptic disorders epitomise the dynamic nature of developmental disorders – whilst brain structure is usually grossly intact, neurophysiological dysfunction constrains cognitive processing leading to adaptive impairments and psychopathology. Synaptic disorders have, by and large, been discovered only within the last decade. The associated neurological and behavioural phenotypes are not yet understood. Clinically-focused characterisation is the first objective of the programme. We will take a cross-domain dimensional approach, focusing on the development of motor skills, communication and social-emotional function. The programme’s second objective is to apply novel online remote testing approaches to investigate dynamic aspects of cognition relevant to learning and behaviour in synaptic disorders. The third objective is to identify neural systems abnormalities in patients with synaptic disorders, via experimental neurophysiology and neuroimaging. The programme will build upon collaborative infrastructure and governance established over the past five years. The programme will draw on Unit-wide experience in cognitive, MEG and MRI methodologies for investigating developmental populations and impaired groups. New within-Unit collaborations will be established to investigate whether similar molecular pathways contribute to lifespan mental health risks across aetiologies. Beyond CBU, projects will continue to rely on an extensive local, national and international network across multiple clinical disciplines to facilitate participant recruitment. Pathways for recruitment have been established from two large UK-wide research cohorts (Deciphering Developmental Disorders, IMAGINE-ID). We will build on existing collaborations with world-leading cognitive and basic neuroscientists and seek to add new arms to this collaboration via animal modelling. In partnership with the Department of Clinical Genetics at Addenbrookes Hospital we will establish a post-diagnostic clinic for synaptic disorders, facilitating research recruitment, enhanced post-diagnostic management, and future therapeutic trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL