Rapid Whole Genome Sequencing Improves Diagnosis
Vienna, Austria: Children who are born seriously ill or who develop serious illness in the first weeks of life are often difficult to diagnose, with far-reaching implications for their short- and long-term care. But whole genome sequencing1 (WGS), performed quickly, can provide an accurate diagnosis and therefore lead to improvements in their clinical management. Results of an Australian study of such use of WGS presented at the European Society for Human Genetics annual conference today (Sunday) show how the integration of genomics, transcriptomics2and functional3 the data can speed up the diagnosis of rare diseases on a national scale.
“The evidence for the diagnostic, clinical and familial benefits of rapid genomic testing in critically ill children is overwhelming. This type of testing should become the standard of care for these patients,” says the presenter, Professor Zornitza Stark, clinical geneticist at Victorian Clinical Genetics Services and Australian Genomics. “And rapid genomic diagnostic programs should continue to drive improvement, innovation and discovery more broadly.”
Researchers performed ultra-rapid nationwide WGS in 290 critically ill pediatric patients with a rare disease between January 2020 and January 2022. They aimed to obtain diagnoses in less than five days. “We wanted the program to serve as an example of how genomics can improve diagnostic and clinical outcomes for pediatric diseases in real time,” says Professor Stark. “We have now integrated RNA sequencing and, through close collaboration with clinicians and researchers, optimized the use of functional data to secure additional diagnostics.”
Ultra-rapid WGS resulted in 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 testing and other tests led to 20 additional diagnoses. New pathogenic genes have also been identified through international matching efforts, and studies are underway to find other diagnoses.
Although the cost of genomic testing remains high compared to other diagnostic investigations, especially when they provide results in rapid turnaround times, their use allows healthcare systems to realize substantial savings in the longer term. Complex, time-sensitive tests such as ultra-rapid WGS are best performed by a multidisciplinary team, which means the skills and capabilities of clinical and laboratory genetics staff need to be developed, says Professor Stark.
“Our approach can serve as a model in other health systems, although it will need to be adapted to local circumstances and evolve over time. For example, Australia has a very geographically dispersed population, which is relatively small compared to land area. It made sense for us to have a central sequencing laboratory for this study, with great attention paid to sample transport logistics and the inclusion of local teams in the analysis via virtual meetings. Different models will be needed in densely populated countries.
“Undoubtedly, there are also adults with rare diseases who would have benefited from ultra-rapid genomic diagnosis but were excluded from the study,” says Professor Stark. Clinical genetics services have traditionally been much more involved in providing consultation in neonatal and pediatric intensive care units, facilitating the identification of patients who would benefit from rapid genomic testing. to access.
Ethical questions are also involved, particularly around consent. Families are overwhelmed and distressed when their child is critically ill, so how best to facilitate informed consent is an issue? Indeed, is consent always necessary? Can it be held? How should the diagnosis of a genetic disease influence the decisions of treating clinicians and families? Are rapid genomic tests a fair use of resources? All of these questions are important and difficult.
“There are still many challenges to overcome, including finding a way to quickly move successful research programs into the clinical setting, but we believe our work has shown that ultra-rapid WGS has diagnostic, clinical and economic benefits. at a national level.” says Professor Stark. “We hope that our approach will soon become part of routine diagnostic practice, not only in Australia, but also further afield.”
Professor Alexandre Reymond, conference chair, said: “Our Australian colleagues are showing us the way forward on how a multidisciplinary approach that rapidly integrates genomic data could become mainstream practice to better serve critically ill newborns. .”
Summary C11.6: Rapid diagnosis of rare diseases on a national scale: an integrated multi-omics approach
1.Whole genome sequencing is the process of determining the complete DNA sequence of an individual, including all chromosomal DNA and that contained in the mitochondria.
2. RNA sequencing (“transcriptomics”) examines the full range of mRNA molecules expressed by an organism. By looking at the entire transcriptome, researchers can determine gene expression.
3. Functional genomics focuses on dynamic aspects, for example, how proteins work, as opposed to static aspects of the genome such as DNA sequence.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of press releases posted on EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.