By Dr Madhuri Hegde, FACMG – SVP and Chief Scientific Officer, Revvity, Inc.
Next generation of genomics
Technological breakthroughs have ushered in the next generation of genomics, enabling clinicians to deliver hyper-personalised, evidence-based prevention and treatment solutions.1
These breakthroughs have enabled researchers to closely investigate an individual’s genetic code, and at a fraction of the time and cost as was previously possible. We already know that detecting the presence of a gene variant, such as the BRCA1 gene associated with breast cancer, can facilitate earlier preventive treatment.2
Early detection of cancer not only saves lives but also can save costs for healthcare systems and contribute to better health outcomes for populations in high-income and upper-middle-income countries.3
None of this would be possible without genomic knowledge.
DNA sequencing methods
In this new era of genomics, there are various methods to investigate a person’s genome that can yield different results. Two methods of DNA sequencing – whole exome sequencing (WES) and whole genome sequencing (WGS) – are widely used in healthcare and research to identify genetic variations.4
Whole exome sequencing allows geneticists to analyse coding regions of the DNA – but it’s well known that certain variants affecting gene function and protein production can occur outside of the coding region.
Whole genome sequencing (WGS), on the other hand, can detect these variations, leading to earlier diagnosis and treatment. This method, when used alongside standard tests, could detect thousands more rare conditions and have a major impact on the quality of life for children born with them.5
This is why various studies are underway to determine the clinical value of more comprehensive sequencing approaches for more patients. For example, the 100,000 Genomes Project has demonstrated success in using WGS to diagnose rare diseases.
While WGS has entered mainstream medicine, cost considerations have hindered widespread adoption.6 Despite this, WGS is becoming a viable option for population-wide screening, with particular interest in newborn screening (NBS).
Every year, thousands of babies around the world are born with rare genetic diseases, which in some cases lead to death or lifelong disability. The earlier that treatable genetic disorders are detected and diagnosed, the more likely it is that early intervention will be possible to prevent disability or other long-term health effects.
Genome sequencing for proactive paediatric screening
Recently, the Journal of the American Medical Association published findings from a study conducted by Revvity Omics that aimed to evaluate the clinical value of using a genome sequencing (GS) approach for the proactive screening of newborns.
A cohort of 562 apparently healthy children were screened by GS, and another 606 with an exome-based panel of 268 genes associated with medically actionable paediatric conditions. Of the 562 children screened by GS, 46 (8.2%) were found to be at risk for paediatric onset diseases, including 22 (3.9%) at near 100% risk of developing the identified disorders (also known as high penetrance conditions).6 In contrast, only 2.1% of the children screened with the exome-based panel were found to be at risk of developing paediatric-onset diseases.7
Implications of the study
The focus of this study was a retrospective analysis to compare the clinical relevance of two conceptually different newborn sequencing approaches: one that is focused only on well-established, medically actionable conditions (the actionable disease-centric approach), whilst the other approach is unbiased to an evaluation of all known disease-causing genes (the genome-open approach).
This is the largest and first real-world proactive screening of apparently healthy children and newborns by clinical genome sequencing that provides a side-by-side clinical comparison of the two conceptually different paediatric screening strategies.
The study showed that a significant proportion of apparently healthy children screened by GS were found to be at risk for a wide range of paediatric-onset conditions likely to be missed on limited gene panels.
A limited-number gene panel, when compared to GS, would have picked up only one-fifth of the high penetrance conditions, many of which are neurodevelopmental disorders that could potentially benefit from early interventions. There is already discussion among the medical community about which genes should be included when screening newborns by sequencing, and this study provides real-world data on what can be learned from WGS.
WGS is gaining broader recognition in society, and, with technological improvements, the cost of DNA sequencing may continue to decrease further. This would make WGS methods more accessible for newborn screening, resulting in easier detection of diseases that would not be identified through a standard biochemical approach.
In turn, we would expect to see substantial impact on the quality of life of children born with treatable genetic disorders, as well as cost savings generated by preventing treatments associated with potential lifelong disability.
There is no doubt that with technological advancements in genetics and medicine the rate of detection and introduction of treatments for rare conditions has grown considerably. This progress will also inform treatment approaches for more common diseases, but there is still more to be done.
As our understanding of genomic sequencing and its implications in diagnostics is continuously evolving, it’s important for us to continue to conduct studies that expand our knowledge to better inform the development of screening programs and diagnostic tools. However, science alone is not enough – we need continuous collaboration between health authorities and governments to ensure that real-world practices are in line with new findings as they occur.
Deloitte. Exploring the future of diagnostics in the UK. Available from: Exploring the future of diagnostics in the UK – Thoughts from the Centre | Deloitte UK. Last Accessed: August 2023
UK Government Office for Science. Genomics Beyond Health Report 2022. Available from: Genomics Beyond Healthcare: future uses and considerations of genomic science – GOV.UK (www.gov.uk). Last Accessed: August 2023
Manchanda R, Sun L, Patel S, Evans O, Wilschut J, De Freitas Lopes AC, Gaba F, Brentnall A, Duffy S, Cui B, Coelho De Soarez P, Husain Z, Hopper J, Sadique Z, Mukhopadhyay A, Yang L, Berkhof J, Legood R. Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems. Cancers (Basel). 2020 Jul 17;12(7):1929. doi: 10.3390/cancers12071929. PMID: 32708835; PMCID: PMC7409094.
Medline Plus. What are whole exome sequencing and whole genome sequencing? Available from: https://medlineplus.gov/genetics/understanding/testing/sequencing/ . Last Accessed: August 2023
Queen Mary University of London. Available at: https://www.qmul.ac.uk/media/news/2022/smd/uk-government-launches-newborn-genomes-programme.html. Last Accessed: August 2023.
Balciuniene J, Liu R, Bean L, et al. At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children. JAMA Netw Open. 2023;6(7):e2326445. doi:10.1001/jamanetworkopen.2023.26445
Servais L. Why we must expand newborn screening. 2021. Oxford News Blog. Available at: Why we must expand newborn screening | University of Oxford. Last Accessed: August 2023.