Applying animal modelling to understand rare novel neurodevelopmental disorders associated with intellectual disability
Intellectual disability (ID) is categorised by a significant reduction in cognitive function and adaptive abilities that begin in childhood. ID is part of a heterogeneous group of neurodevelopmental conditions associated with impairment in developmental domains and a cause of particularly adverse socioeconomic impact worldwide. There have been many recent advances in identifying causative genetic mutations in previously unexplained ID cases. With these advances comes an increasing demand for understanding mechanisms underpinning these pathogenic pathways. In this PhD thesis, I have studied rare monogenic novel neurodevelopmental disorders associated with ID. The objective of the thesis was to model a subset of mutations associated with novel neurodevelopmental disorders in mice to demonstrate a causal link between mutation and phenotype and to further understand the mechanisms by which these mutations result in human neurodevelopmental disorders. In order to achieve this, I adopted a multi-phase approach. Firstly, I designed a phenotyping platform, by combining behavioural and cognitive tests with morphometric brain analysis and genome-wide transcriptional analysis. I then used this approach to study KPTN-related syndrome, a novel developmental disorder that to date has not been characterised in mice, successfully recapitulating the main phenotypes described in the patients. Moreover, I gained further insight into the underlying pathogenic mechanisms associated with the disorder, opening the possibility of a therapy that could treat some aspects of cognitive and morphological impairments identified in the patients with KPTN-related syndrome. Lastly, I determined whether such an approach could be scaled-up to study multiple novel neurodevelopmental disorders, each with a mutation associated with a haploinsufficient novel neurodevelopmental disorder. I identified specific phenotypes for each of the four mouse lines under investigation, providing a platform for comparison between several developmental disorders. These refinements contributed to a larger five-year project starting at the Sanger Institute, aimed at characterising a wider diversity of human neurodevelopmental disorders.