Project - The investigation of motor neurone disease candidate gene variants
Research Project Description
To date, around 40% of familial MND cases and 90% of sporadic MND cases have an unknown genetic cause. Hence, this project aims to identify novel candidate genes and variants causing MND in familial and sporadic cases using novel gene discovery approaches and next-generation sequencing data.
Candidate gene screening in Australian sporadic and familial MND cases:
This involves screening recently implicated MND genes in our Australian MND cases to identify known or novel variants that could be causing disease. This is important to identify the frequency of known MND variants in our Australian cohorts, and to identify novel variants in disease-associated genes. Using Unix and R scripts, genes of interest are filtered for novel non-synonymous variants for further analysis and validation. Moreover, gene-based burden analysis is carried out for each gene to determine whether there was an over- or under-representation of rare variants in MND cases compared to healthy controls. Genome-wide burden analysis comparing cases to controls will also be performed to identify disease-associated genes.
Novel gene discovery in small MND families:
In recent years, the genetic cause of most large MND families have been solved, with typically small families remaining. This project investigates small families, with insufficient power for significant linkage and segregation analysis. A novel gene discovery pipeline developed by our lap is being applied to these families to identify the disease-causing gene. This pipeline includes analysis and standard filtering of genetic data, in silico prioritisation (protein prediction tools, conservation analysis, natural variation, gene expression, burden analysis, association testing), and in vitro functional studies using cell models.
Genetic analysis will also be extended to analyse structural and copy number variants that could be causing disease in these small families. Indeed, these types of variants have been associated with other neurodegenerative disorders and developmental conditions such as schizophrenia, Alzheimer’s disease, Parkinson’s disease, and MND, and are therefore of significant importance to MND.
Finding novel genes and variants is crucial as genetic diagnostic screening can include these new genes so that early support and care can be provided to early- or even pre-symptomatic patients. Genetic research can also help to improve our understanding of the disease mechanisms underlying MND, as well as help identify targets for effective therapeutic treatments.
Key Publications from this project
Chan Moi Fat, et al. "Genetic analysis of GLT8D1 and ARPP21 in Australian familial and sporadic amyotrophic lateral sclerosis." Neurobiology of Aging (2021).