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Diagnostics Genetics and epigenetics, Clinical care, Technology and innovation

A Rare Resolve

Credit: National Cancer Institute /

Children with suspected genetic conditions need a quick diagnosis – speed can mean the difference between life and death. And though results from clinical genomic testing often take several months, The Acute Care Genomics program integrates whole genome sequencing with multiomics to improve diagnostic outcomes (1). They found that the combination of transcriptome sequencing, functional studies, and research-based analyses for new gene variant types greatly increased diagnostic yield. What role does multiomics play in the future of rare disease diagnostics? 

We spoke with Zornitza Stark, Clinical Research Fellow at Australian Genomics and co-author of the study, to explore outcomes, future directions, and ethical considerations. 

Why is a quick diagnosis so important for those with rare diseases?

Rare diseases are estimated to affect 300 million individuals worldwide. In high-income countries, rare diseases are a leading cause of child hospital admission, disability, and mortality. Historically, diagnosis has only been achieved for a very small proportion of affected individuals after many years of specialist assessments. Over the past 10 years, the introduction of genomic sequencing has transformed clinical care by providing a faster and more accurate diagnosis. A quick diagnosis obviates the need for a wide range of expensive and frequently invasive tests, relieves uncertainty, enables access to appropriate support, and provides parents with information about the chance of recurrence in future pregnancies. For an increasing number of individuals, genomic diagnosis also provides access to precision treatments.

Please introduce The Acute Care Genomics program…

The Acute Care Genomics program is an Australian research study that set out to evaluate the impact of ultra-rapid genomic diagnosis for critically ill babies and children with suspected rare diseases. Typically, results from clinical genomic testing take several months. However – to improve the care of critically ill babies and children – genomic testing needs to be delivered within a matter of hours and days, not weeks and months. Quick results have been demonstrated by several centers worldwide, but we wanted to scale up to a national level, so that critically ill babies or children with rare diseases in Australia could have access to a timely diagnosis.

How do WGS and multiomics work together to provide the best outcomes?

Whole genome sequencing (WGS) is well suited to ultra-rapid testing because of its ability to assess multiple variant types in a single test. WGS removes the need to perform genetic tests, such as chromosomal microarray or mitochondrial DNA testing, sequentially. However, it also generates vast amounts of data – and our sequencing ability currently still outstrips our ability to accurately detect and interpret many genetic variants. Integration with multiomic approaches, such as transcriptome sequencing and proteomics, holds the promise to further improve diagnostic outcomes by clarifying the functional consequences of DNA variants.

Could you summarize the findings of your research?

The Acute Care Genomics program provided ultra-rapid WGS to 290 critically ill babies and children with rare diseases over a period of two years. Recruitment covered all Australian states and territories, including all children’s hospitals in the country. Over half of our patients were younger than one month, and presented a wide range of clinical issues, including seizures, congenital malformations, and unexplained organ failure. All WGS results were delivered in under five days, with an average time to result of 2.9 days (the fastest time was 45 hours). The diagnostic yield of clinically accredited WGS was 47 percent. Rapidly incorporating additional bioinformatic analyses, transcriptome sequencing, and functional validation of variants of uncertain significance increased the diagnostic yield to 54 percent. Timely diagnosis had a major impact on clinical care, and informed precision treatments, surgical and transplant decisions, and palliation in 60 percent of those diagnosed.

What are the next steps in your research?

Our priority is to ensure that the results of this study are translated equitably into clinical practice. The diagnostic and clinical utility of rapid genomic testing in critically ill babies and children with rare diseases has been demonstrated by multiple studies in a variety of healthcare systems, and it is time for it to become the standard of care. From a research perspective, I am most excited about long-read sequencing, which has the potential to further shorten time to result and provide a more comprehensive variant detection.

What are the ethical considerations? 

Genomic testing raises many ethical issues. Testing with rapid turnaround times raises concerns about the ability of parents to process complex information and provide informed consent at a time when their child is critically ill. There are also concerns about how results may impact parent–child relationships and bonding. Our multidisciplinary research team has explored these ethical issues in depth through surveys, interviews, and focus groups with families and health professionals. The outcome of these have been published separately (2). This research has continually informed the role of genetic counselors and supported the development of a range of resources, including pre- and post-test counseling. 

Will the integration of genomic, transcriptomic, and proteomic data become standard practice in clinical settings?

Integrating genomic, transcriptomic, and proteomic data occurs on a small scale – largely as part of dedicated research programs designed to seek answers in highly selected patients with rare disease at the end of the diagnostic odyssey. We need to integrate these approaches into standard laboratory practice to fully capitalize on the diagnostic potential of genomic sequencing. The transition to diagnostic practice will require appropriate funding and assay validation but will also ensure reproducibility and timeliness of results.

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  1. S Lunke et al., Nat Med, [Online ahead of print] (2023). PMID: 37291213
  2. Christopher Gyngell et al., Pediatrics, 143 (2019). PMID: 30600266
About the Author
Georgia Hulme

Associate Editor for the Pathologist

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