The development of the fetal brain relies on the timely production of neurons, their correct placement as well as their capacity to form the appropriate connections with other brain cells. Abnormal formation of the brain during pregnancy can lead to structural brain abnormalities, a collective term referring to disruptions in the development and functional organisation of neural circuits which subserve mental function. Structural brain abnormalities are recognised to underlie childhood neurodevelopmental conditions such as epilepsy, intellectual disability and autism. In Australia, the total cost of intellectual disability alone is estimated to exceed AUD$14billion annually, with opportunity cost of lost time accounting for 85% of family expense.
Children born with structural brain abnormalities can experience severe difficulties with everyday living, and each child may need complex multidisciplinary and personalised care to achieve their best outcomes. Because the parts of the brain which govern our senses including sight, smell, hearing and tasting are compartmentalised into functional regions, the consequences of structural brain abnormalities on a child’s mental capabilities are not straightforward to diagnose. Equally, it is often a struggle to arrive at a definitive diagnosis as to the cause of their brain condition. Indeed, the ability to provide a clinical interpretation of DNA sequencing data remains a significant challenge, and healthcare professionals are more often presented with a genetic “Variant of Uncertain Significance (VUS)”, typically with limited experimental data to aid in its interpretation.
Our laboratory applies functional studies to establish the causative nature of genetic mutations in structural brain abnormalities.
Project 1) How does genetic variation to ZBTB18 (aka ZNF238/RP58) influence brain development and disorder?
Recent improvements in genome sequencing technologies have empowered researchers and clinicians with a means to investigate the genetic basis for neurological disorders that result from copy-number variation (CNV). However, what continues to remain a challenge is to establish the pathogenicity of genomic abnormalities, such as CNVs, and their causative effects on nervous system impairment. In this project, we clarify possible genotype-phenotype relationships in human subjects with brain developmental disorder which are associated with microdeletions to 1q43-44. Our investigation has led to the identification of ZBTB18 as a critical gene for brain development. Using a range of molecular and cellular approaches combined with in utero electroporation with mice, the goal of this project is to understand how loss of ZBTB18 leads to impairments in the production of cerebral cortical neurons during fetal development. This work leads to an improved understanding of the molecular basis for 1q43-q44 CNVs in human health and mental dysfunction.
Project 2) Harnessing Human Genetics to Discover Novel Molecular Pathways for Brain Development and Neuronal Homeostasis
During fetal development, the growth of the cerebral cortex relies on a step-wise process of neurogenesis, cell migration and circuit formation. Failures in these key developmental steps can result in brain disorder and lead to intellectual disability. The goal of this project is to study the neurobiology of brain development disorders with a genetic origin, as well as to characterise novel players in brain development and disease. Through this research, we will better understand the molecular and cellular functions within the developing brain which guide the development of new neural circuits as they fire and wire appropriately. We will apply this knowledge towards developing tools which improve the genetic diagnosis and clinical management of patients born with brain disorders such as epilepsy, intellectual disability and autism. We have collaborated with researchers from across the world to report on disease-causing mutations to genes including TUBB5 (aka TUBB), DENR, TBCD and NPRL3.
Project 3) Understanding the cellular and molecular basis for neuronal migration during brain development and disease
Migration is a universal property of all newborn neurons of the developing mammalian nervous system (Heng et al, 2010, TiNS). In this project, we will study the functions for protein-coding genes which regulate the ability for immature neurons of the cerebral cortex to position themselves appropriately within the growing fetal brain. We will apply these findings to understand the genetic basis for neuronal migration disorders in humans.