Meet the Expert: Professor David Thorburn

Introduction

• Professor David Thorburn is a leading researcher specialising in genetics and mitochondrial disease (mito), and his team has helped over 700 people with suspected mito get a diagnosis (00:02:58).
• Mitochondrial diseases are a group of rare diseases that affect the power plants of the cell, with over 400 different genes that can underlie the condition, and are complicated to diagnose due to the large number of genes involved (00:04:37).
• The diagnosis of mito is significant as it can help guide treatment and care, provide access to support services, and link to research and clinical trial opportunities, with the mitoMDT project aiming to increase diagnosis rates by 70% (00:02:12).
• Genomics has revolutionised the diagnosis of mito by allowing for the examination of all 20,000 genes at once, rather than one gene at a time (00:10:21).

Advances in Genetic Diagnosis

• Prior to 2010–2015, genetic diagnosis was only possible in 10–20% of patients, but with the advent of new technologies, including genome sequencing, this number has increased to around 50% (00:12:10).
• The use of genomics, transcriptomics, proteomics, and metabolomics has transformed the field of diagnosis, enabling researchers to better understand the underlying causes of disease and making it possible to diagnose conditions from a blood sample (00:14:08).

The mitoMDT Project

• The mitoMDT project is a national project funded by the Medical Research Future Fund, aiming to lift the diagnostic rate in individuals with rare diseases to over 70% (00:19:58).
• The project involves expertise across Australia and international collaborators, recruiting patients with suspected mito and applying innovative interdisciplinary approaches (00:20:24).
• The project has recruited 125 individuals, with the majority being children, and has involved various research and diagnostic sites, including the Centre for Population Genomics and the Murdoch Children’s Hospital (00:25:51).
• Eligibility for the project was defined using the modified Nijmegen criteria.(00:24:25).

Project Highlights and Successes

• The project has had some successes, including the use of proteomics to gain a diagnosis in about 10 or 12 patients so far, but it’s still early days with only about half of the patients having undergone genomic testing (00:28:44).
• Proteomics has been a significant highlight, enabling ultra-rapid variant prioritisation in mitochondrial and other rare diseases, with the potential to solve cases that were previously unsolved through genomic testing alone (00:29:05).
• The proteomics method can provide results within a 3-day timeline, allowing for rapid diagnosis and cost savings, and has been shown to be effective in solving cases of rare diseases, including mito (00:30:08).
• A recent study published by Daniella Hock, David Thorburn, David Stroud and others has demonstrated the effectiveness of untargeted proteomics in enabling ultra-rapid variant prioritisation, with the goal of implementing this method into clinical practice (00:31:08).

Interpreting Results and Analysing Data

• Genome sequencing is used to diagnose inherited diseases, and guidelines from organisations like the American College of Medical Genetics and Genomics inform the interpretation of results (00:39:23).
• Clinical labs analyse genome sequencing data using rules and guidelines, and they typically focus on a subset of genes, such as the approximately 400 genes linked to mito, when investigating a specific condition (00:41:25).
• The use of automated reanalysis programs and databases like gnomAD, which contains data from over 100,000 individuals, helps to identify relevant genetic changes and improve diagnosis rates (00:44:49).

MitoDiscoveries and Differences

• Researchers have been studying suspected mitoin various cohorts, including retrospective analyses, and have been using a confidential database to store results (00:47:43).
• International collaboration is increasing diagnostic rates. A recent query from the Centre for Population Genomics about a change in a gene led to the discovery of 140 patients with a completely novel mechanism of disease, some of whom were initially thought to have mito(00:48:30).
• The causes of mito differ between children and adults, with mitochondrial DNA mutations being a minor cause in children, but a more significant cause in adults (00:50:43).

• Genetic testing can detect mitochondrial DNA variants, and labs like VCGS report the level of heteroplasmy, which can vary between tissues, such as blood and muscle (00:53:06).

Ongoing Research and Confirming Diagnosis

• Research is ongoing for various genes, including the PMPCB gene, which is involved in protein processing in the mitochondria, and functional studies are being conducted in Australia and elsewhere (00:55:37).
• A genomic diagnosis is necessary to confirm mito, as some conditions have similar overlaps (00:56:50).

Additional Support

• Resources are available on the Mito Foundation website and Helpline for those interested in learning more about diagnosis and clinical studies related to genetics and mito (00:57:34).