GENOMICS
Unlike targeted genetic panels or biochemical assays, WGS reads an individual’s entire genome, enabling clinicians to detect a much wider range of conditions, including those not currently covered by standard screening programmes
(SCID) demand urgent diagnosis to be effectively managed. Genomic screening not only increases the detection rate for such conditions but also allows clinicians to personalise care based on the specific variant identified. Furthermore, a rapid turnaround time (ideally less than five days) can be the difference between early intervention and missed opportunity. Ultra-rapid WGS protocols are now demonstrating such timelines, even in acute neonatal settings.5
Operationalising genomic screening
Implementing WGS-based newborn screening at scale requires significant operational capabilities. From a laboratory perspective, the key enablers include: n Automated high-throughput workflows for DNA extraction, library preparation, and sequencing from multiple sample material such as dried blood spot, blood and saliva.
n Cloud-based bioinformatics pipelines capable of real-time variant calling and prioritisation.
n Clinically validated reporting systems that translate raw sequence data into actionable insights.
Collaborative programmes in the UK and other countries are leveraging this infrastructure to demonstrate the feasibility of integrating genomics into routine newborn care. These efforts
underscore that the challenge is not simply sequencing more genomes, but doing so reliably, ethically, and at scale.
Ethical and social considerations Introducing genomic testing at birth raises important ethical questions, particularly regarding consent, data use, and the return of results. Unlike traditional NBS, which typically reports only actionable childhood-onset disorders, WGS may uncover information about adult-onset diseases, carrier status, or variants of uncertain significance (VUS). Determining which results to report, and when, is an area of ongoing debate. To address these concerns, most
programmes are adopting a ‘targeted return’ model: reporting only variants associated with childhood-onset, treatable disorders unless parents opt in for broader findings.6
Clear, structured
consent processes – supported by educational resources – are critical to ensuring parental understanding and autonomy. Long-term data storage and reanalysis policies also need ethical scrutiny. While genomic data could offer lifelong clinical utility, they also require robust safeguards for privacy, data access, and future re- consent.
Interpretation challenges and the role of reanalysis WGS generates a vast amount of data, much of which is initially uninterpretable.
The clinical significance of many rare variants remains unknown and even well-characterised mutations can have variable penetrance. This makes variant interpretation a bottleneck for genomic screening. To mitigate these challenges, laboratories rely on curated variant databases, multidisciplinary review boards, and international knowledge-sharing platforms. Moreover, periodic reanalysis of stored genomic data allows previously ambiguous variants to be reclassified in light of new evidence, enhancing long-term diagnostic yield.7 Importantly, genomic screening must balance sensitivity and specificity. Over- reporting uncertain or low-penetrance variants could increase parental anxiety or lead to unnecessary medicalisation. Thus, analytical pipelines must prioritise clinical validity and utility over mere detection capability.
Cost considerations and health system impact
While WGS costs have fallen dramatically over the past decade, they remain higher than traditional NBS. However, cost- effectiveness analyses suggest that early genomic diagnosis can lead to significant long-term savings: by avoiding diagnostic odysseys, preventing disease progression, and reducing intensive care stays.8 For healthcare systems, the investment in genomic screening must be weighed against downstream cost offsets and the broader societal benefits of early intervention. Pilot studies are already demonstrating that WGS-based NBS can identify treatable conditions that would otherwise go undetected, leading to improved outcomes and economic efficiency.9
Future directions Genomic screening at birth lays the foundation for lifelong precision health. The data generated can inform not only
WWW.PATHOLOGYINPRACTICE.COM SEPTEMBER 2025
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