Neurodevelopmental disorders (NDD) are a subset of rare diseases. NDDs are characterised by the impaired function of the central nervous system during development and across multiple neurological facets such as motor and communication skills, cognition, and behaviour. Approximately 2-5% of children are estimated to be born with or develop a NDD during childhood, and in developed countries, NDDs are mostly genetic in cause. Despite growing access to genetic testing, and better knowledge of the genes involved, only ~50% of affected individuals gain a precise genetic diagnosis following a genetic test.

Investigating the pathogenicity of variants suspected to cause genetic disorders benefits from functional studies analysing the products of gene expression. The genetic diagnosis of Neurodevelopmental Disorders (NDDs) is limited by the brain-restricted expression of NDD genes, which are not expressed in routinely assayed diagnostic tissues (blood or skin). To gain access to these brain-restricted gene products, my PhD will develop and apply cellular reprogramming technologies. Direct cellular reprogramming will enable the conversion of human dermal fibroblasts generated from patient skin biopsies into neurons and astrocytes. RNA-based studies of these variants in disorder relevant cell types will provide functional evidence to help reclassify these variants as pathogenic or benign, thus enabling better access to support services, treatments, and clinical trials for patients. 

iNeurons generated from patient fibroblasts over three weeks. TUBB3 (red), MAP2 (green), PSA-NCAM (blue).