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Diagnostics Omics, Screening and monitoring

Ode to WGS

Credit: Revvity

The next generation of genomic technologies is already transforming the diagnosis and treatment of rare diseases by enabling researchers to investigate a person’s genetic code and develop hyper-personalized solutions. With increased investment, scientists are breaking new ground in genomics – and providing fresh hope for patients in need of diagnosis and access to treatment. In November 2023, the UK Government released a statement committing funds to several different research projects that could bring researchers one step closer to unleashing the potential of genomic technologies in clinical settings.

Among the funding commitments in the UK Government’s statement, £51 million was announced for the Our Future Health initiative, which will recruit one million patients to take part in genomic research. Further investment was allocated to Genomics England to launch the Rare Therapies Launch Pad, which aims to generate evidence for new therapy pathways for children with ultra-rare diseases. Additionally, research and development tax reforms were announced to improve incentives for scientific innovation, benefiting companies working in genomic technology.

These upcoming investments are particularly promising for researchers working in whole genome sequencing (WGS) – a key technique used in genomics. Though whole exome sequencing (WES) allows geneticists to analyze the protein coding regions of the DNA, WGS can also detect variants affecting gene regulation and protein function that occur outside of the coding region. WGS provides higher clinical yield than exome sequencing and microarray testing combined, which could help scientists detect thousands of rare conditions earlier, improving the quality of life of patients.

Diagnosing a higher number of highly penetrant conditions

In newborn screening, WGS has been able to identify more cases of lifelong genetic conditions than exome-based screening. Recently, the Journal of the American Medical Association published findings from study – conducted by Revvity Omics – that evaluated the outcomes of two conceptually different newborn screening approaches: one using genome sequencing as a proactive screening approach and the other using an exome-based gene panel for medically actionable childhood-onset conditions (1). The study is the first real-world proactive screening of apparently healthy children and newborns that provides a side-to-side comparison of the conceptually different screening strategies. 

The study found that of the 562 children screened by WGS, 46 (8.2 percent) were at risk for pediatric-onset diseases – of which 22 (3.9 percent) were at risk of developing high penetrance disorders. By comparison, of the 606 children screened with the exome-based panel only 13 (2.1 percent) received diagnoses of potential childhood-onset conditions.

These results indicate that, when compared with a limited gene panel, whole genome sequencing uncovered a significantly higher number of pediatric-onset diagnoses. Many of these diagnoses involved high-penetrance, often neurodevelopmental disorders that would benefit from early intervention and disease surveillance. A gene panel that was limited in scope would have identified just ~20 percent of these high-penetrance conditions, leaving the remaining ~80 percent of conditions undetected.

Potential for population-wide screening

WGS is an increasingly viable technique that holds the potential to evolve from its current use – which is primarily in research – to clinical use. 

Ongoing studies should provide further evidence of the cost-effectiveness, feasibility, and clinical utility of genome sequencing in clinical settings, including newborn screening programs. Genomics England has already led the way with the 100,000 Genomes Project – an initiative launched in 2018 that, as the name suggests, sequenced over 100,000 genomes to study their role in rare diseases and cancer. As well as uncovering new diagnoses in 25 percent of participants, the study generated a vast dataset to inform researchers, policymakers, and healthcare leaders of the value of integrating WGS in routine healthcare. Analysis of this data is set to continue for many years to come, helping scientists design screening programs using WGS to bring treatments, diagnostics, devices, and medicines to patients sooner.

Implementing WGS in newborn screening programs can increase the chances of doctors diagnosing rare disorders not detected by biochemical screening, and intervening earlier in the lives of babies born with them – preventing lifelong disability and other long-term health effects. Diagnosing and managing these conditions will not only transform healthcare outcomes for these children and their families, but also save healthcare systems the associated costs.

Though the detection rate of rare diseases is growing thanks to technological advancements in genetics, further studies over the coming years will help inform the development of screening programs and diagnostic tools. The advancements in genomics made possible by the UK’s recently announced investments are an important step towards greater adoption of WGS in mainstream medicine in the UK, unlocking potential for more widespread implementation worldwide.

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  1. J Balciuniene et al. JAMA Netw Open, 6, 7 (2023); e2326445. PMID:37523181.
About the Author
Madhuri Hegde

Senior VP and Chief Scientific Officer at Revvity

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