Graduate Research Degree Awarded - Tian (Teresa) Zhao
Congratulations to Tian (Teresa) Zhao - Doctor of Philosophy Awarded 15 September 2026
Degree: Doctor of Philosophy
Supervisors: Prof. John Christodoulou, A/Prof. David Stroud, Prof. David Thorburn
Advisory Committee: Prof Clara Gaff (chair), Dr Meg Wall
Thesis Title: Reshaping Genomic Medicine Through the Lens of Functional Genomics
Thesis Summary:
Rare diseases collectively affect approximately 400 million people globally. In Australia, 8% of the population are affected, this means about 2 million Australians are currently living with a rare disease. Individuals affected by a rare disease often experience a long diagnostic odyssey.
The current diagnostic paradigm is very much genomics driven. Next Generation Sequencing (NGS) has revolutionised rare disease diagnostics. In addition to short read NGS, Long Read Sequencing (LRS) can also be deployed to assist in genomic diagnosis. Despite this great success, nearly half of children with a rare genetic disorder remain undiagnosed. One of the major contributors to this is the absence of functional evidence to confirm the pathogenicity of a potentially relevant but novel variant. Clinically validated and available disease agnostic functional tests are needed to fulfill this gap. Mass spectrometry-based proteomics has received growing attention in the last two decades due to its large-scale and high-throughput nature. It has started taking centre stage in providing functional solutions for rare disease diagnosis, however its validation as a potential orthogonal clinical tool is lacking.
The aim of my project was to investigate the potential of untargeted proteomics in the study and diagnosis of rare diseases. Three cohorts of patients were recruited. First, a retrospective study of 23 already diagnosed rare disease patients were recruited through the RDNow project. With the analyst blinded to the diagnosis, this cohort was employed to demonstrate the clinical utility of proteomics in arrange of genetic conditions. Second, 13 undiagnosed patients from the UDP-Vic cohort were recruited to investigate the potential limitations of MS-based proteomics in the clinical diagnosis of patients with negative NGS and RNAseq results. Third, a cohort of 15 patients recruited to UDN-Aus, a collaborative, national undiagnosed disease network was used to validate clinical proteomics across multiple rare diseases prospectively.
Patient samples (peripheral blood mononuclear cells, skin fibroblasts or lymphoblasts) were collected and processed for study. A three-tiered analysis process was developed to investigate candidate proteins based on their: 1) protein abundance of lead gene, 2) for multi-subunit protein complexes, changes in abundance of other proteins in the complex, and 3) changes in abundance of interacting or binding partners noted in the published literature.
The results were used to inform pathogenicity of variants in the candidate gene. To date, we have found that about 64% of the cases had proteomic results supporting pathogenicity of the candidate variants, allowing us to confidently reclassify genomic variants, thereby contributing to a genomic diagnosis. Some of our cases had novel disease genes, necessitating the need for further clinical and functional validation to be confident that these genes are truly the cause of the phenotype in these individuals.
Overall, this assay will benefit patients by providing additional information on the functional impact of the variants identified. This cost-effective and time-efficient approach will increase diagnostic yield and improve the management of individuals affected by a rare disorder. A single high-throughput proteomics test will revolutionise the approach to diagnosing rare diseases, end the diagnostic odyssey endured by many Australian families, restore their reproductive confidence, and for some affected individuals, will potentially allow access to targeted therapies.
Date awarded: 15 September 2026
