Rapid results for DNA disorders
Ultra-rapid DNA sequencing is helping diagnose critically ill kids in just 3 days.
New Australian research offers a glimpse into the future of diagnostics.
Children who are born severely ill or who develop serious illness in the first few weeks of life are often difficult to diagnose, with considerable implications for their short and longer-term care.
However, whole genome sequencing (WGS), carried out rapidly, can provide an accurate diagnosis and lead to improvements in their clinical care.
In a recent Australian study, rapid WGS of 290 critically ill children saw just under half receive a diagnosis in less than 3 days.
“The evidence of diagnostic, clinical, and family benefit of rapid genomic testing in critically ill children is overwhelming. This type of testing should become the standard of care for these patients,” says Professor Zornitza Stark, clinical geneticist at the Victorian Clinical Genetics Services and Australian Genomics.
“And rapid genomic diagnosis programmes should continue to drive improvement, innovation, and discovery more broadly.”
She led the research team that carried out nationwide ultra-rapid WGS in 290 critically ill paediatric patients with rare disease between January 2020 and January 2022. They aimed to have diagnoses in less than five days.
Ultra-rapid WGS resulted in a diagnosis in 136 patients, with an average time to diagnosis of just under three days. Of the 154 patients who were not diagnosed by standard WGS analysis, RNA sequencing, functional assays and other tests led to an additional 20 diagnoses.
Whole genome sequencing is the process of determining the complete DNA sequence of an individual, including all the chromosomal DNA and that contained in the mitochondria.
RNA sequencing (‘transcriptomic’) looks at the full range of mRNA molecules expressed by an organism. By looking at the whole transcriptome, researchers can determine gene expression.
New disease-causing genes were also identified through international matchmaking efforts, and studies are underway to find further diagnoses.
“We wanted the program to serve as an exemplar of how genomics can improve diagnostic and clinical outcomes in paediatric disease in real time,” says Prof Stark.
“We have now incorporated RNA sequencing and, through close collaboration with clinicians and researchers, optimised the use of functional data to secure additional diagnoses.”
Although the cost of genomic testing remains high compared with other diagnostic investigations, particularly when delivering results in rapid turnaround times, its use provides substantial savings to healthcare systems in the longer term.
Prof Stark says that complex, time-critical tests such as ultra-rapid WGS are best delivered by a multidisciplinary team, and that means that both capacity and capability in the clinical and laboratory genetics workforce need to be grown.
“Our approach can serve as a model in other healthcare systems, although it will need to be adapted to local circumstances and to evolve over time,” she said.
“For example, Australia has a very geographically dispersed population, which is relatively small compared to the land area. It made sense for us to have a central sequencing laboratory for this study, with a lot of attention paid to sample transport logistics and to including local teams in analysis through virtual meetings. Different models will be needed in countries with high population density.”
The findings were presented to the annual conference of the European Society of Human Genetics.