The Harry Perkins Institute of Medical Research, Perth, Western Australia
The functions of the human brain are predicated on the correct assembly of neural circuits during development. Failures in this process can lead to brain disorders including epilepsy, intellectual disability and autism. Over the last decade, significant advances in DNA sequencing have facilitated the detection of causative mutations in brain disorder. However, it is apparent that a significant majority of detected mutations have unknown pathological consequences, termed "variants of unknown significance" (VOUS). Crucially, existing computational-based methods for evaluating VOUS are limited by a lack of experimental data. The prevailing hypothesis is that a significant proportion of VOUS to known and novel genes are pathogenic for brain disorder. In this presentation, I will discuss our recent work to establish the causative nature of VOUS in human brain disorder. In particular, our work on VOUS to protein-coding genes has led to the identification of new molecular players which influence neuronal migration, an essential first-step undertaken by newborn neurons in order to assemble as functional circuits in the brain. Our work aligns with the clear and unmet need to establish the causative nature of VOUS in brain development and neurodevelopmental disorder.