Researchers at the University of Melbourne have developed a groundbreaking blood-based diagnostic test that could transform the diagnosis of rare genetic diseases in children, offering results in under three days using just one milliliter of blood from infants. The proteomic test, presented at the European Society of Human Genetics conference, addresses a critical gap in current diagnostic capabilities where approximately half of all patients with suspected rare diseases remain undiagnosed.
Addressing a Global Health Challenge
Rare genetic diseases collectively affect around 300 million people worldwide, with over 7,000 different types caused by mutations in more than 5,000 known genes. Dr. David Stroud, co-author of the study from the University of Melbourne, explained the current diagnostic challenges: "In most cases people suspected of a rare disease undergo genomic testing, which revolutionised their diagnosis, but typically only leads to a diagnosis about 50% of the time."
Those who don't receive a diagnosis from genomic testing often face what Stroud describes as a "diagnostic odyssey" lasting months to years, involving numerous invasive tests including muscle biopsies that require general anesthesia in children, carrying inherent risks.
Revolutionary Proteomic Approach
The new test, developed by Dr. Daniella Hock, a Senior Postdoctoral Researcher at the University of Melbourne, and her team, sequences proteins rather than genes themselves. This proteomic approach analyzes thousands of proteins in a single, untargeted test to understand how genetic changes affect protein function and lead to disease.
"Our new test can identify more than 8,000 proteins in peripheral blood mononuclear cells (PBMCs) covering more than 50% of known Mendelian and mitochondrial disease genes, as well as enable us to discover new disease genes," Dr. Hock stated.
The test applies to potentially thousands of different diseases and can even detect new ones by providing evidence needed to confirm that a genetic change is the likely cause of disease.
Enhanced Diagnostic Performance
According to Prof. David Thorburn, another author of the research from the University of Melbourne, the new approach significantly improves diagnostic capabilities: "Genomics is the frontline test and it can solve the diagnosis in about 30-50% of patients suspected of a rare disease. We think a single proteomic test can increase that diagnostic yield to 50-70% of suspected patients."
The researchers found that their approach outperformed current gold-standard tests for mitochondrial diseases used alongside genetic testing and enabled diagnosis of diseases where genomic testing alone had been unsuccessful.
Trio Analysis and Clinical Benefits
When performed on blood samples from both the patient and parents, called trio analysis, the test significantly improves differentiation between carriers who have one copy of the defective gene and affected individuals who carry two copies in recessively inherited conditions.
"The ability to use so little blood from infants and to produce robust results with a rapid turnaround time has been revolutionary to families," Dr. Hock noted. "Using familial samples for trio analysis greatly improves the differentiation between carrier and affected individuals with higher confidence, and that has exceeded our initial expectations."
Cost-Effectiveness and Clinical Implementation
A recent study conducted in collaboration with the Melbourne School of Population and Global Health revealed that implementing the test in clinical settings would have similar costs to current tests used for diagnosing rare mitochondrial diseases, with the significant advantage of potentially diagnosing thousands of other diseases.
For mitochondrial diseases specifically, the test requires only 1ml of blood from newborns compared to current techniques involving muscle biopsies. While focused on mitochondrial diseases in the current study, Stroud indicated the test is already applicable to about half of the 7,000 known rare diseases, though more work is needed to demonstrate this broader applicability.
Expert Validation and Future Prospects
Michal Minczuk, professor of mitochondrial genetics at the University of Cambridge, who was not involved in the study, praised the research: "Overall, the paper marks a very significant step forward in diagnostic practices by introducing a robust, rapid, and minimally invasive method for confirming and characterising genetic disorders. This could greatly enhance patient care by expanding the tools available for clinicians and researchers in genomic medicine."
Robert Pitceathly, professor of clinical neurology and mitochondrial medicine at UCL Queen Square Institute of Neurology, agreed on the significance while noting next steps: "The next step is broader validation and integrating this technology into NHS diagnostic services to improve patient outcomes."
The researchers hope their test will become a standard diagnostic procedure for rare genetic diseases in clinical laboratories, potentially bringing considerable benefits to patients, families, and healthcare systems by reducing diagnostic time and avoiding unnecessary invasive procedures.
