By uncovering life-altering genetic conditions before symptoms appear, genomic screening could redefine newborn care if health systems can scale the technology responsibly.
Study: Feasibility, acceptability and clinical outcomes of the BabyScreen+ genomic newborn screening study. Image Credit: Sergei Drozd / Shutterstock
In a recent article in the journal Nature Medicine, researchers explored the feasibility of incorporating WGS into NBS for 1,000 Australian infants. While standard screening identified hypothyroidism biochemically in one infant, incorporating WGS clarified the genetic cause in that case and increased this number to 16 high-chance findings, allowing parents and healthcare providers to modify care accordingly. Parents also found the procedure acceptable and did not appear to regret consenting to the screening.
Background
NBS has long been an effective public health intervention, enabling early detection and treatment of rare, serious conditions. However, traditional NBS relies on biochemical markers, which limit the range of detectable disorders and often lag behind advances in precision medicine.
The growing capabilities of genomic sequencing offer the potential to vastly expand NBS by identifying hundreds of genetic conditions, including those without biochemical indicators, and to enable lifelong data reuse for diagnosis and research.
Despite its promise, genomic newborn screening (gNBS) raises several implementation challenges, such as determining which conditions to include, how and when to obtain consent, the optimal testing method, and how to manage healthcare system implications. Internationally, few prospective studies have provided real-world evidence to guide policy.
Recently launched programs such as GUARDIAN (USA) and BabyDetect (Belgium) are exploring feasibility at scale. In Victoria, Australia, the BabyScreen+ study was designed to address key knowledge gaps by testing the practicality, clinical value, and psychosocial impact of offering WGS-based newborn screening for 605 genes linked to early-onset, treatable genetic conditions within a public healthcare setting, alongside standard biochemical NBS.
About the Study
The BabyScreen+ study was a prospective cohort project conducted in Victoria, Australia, to test the feasibility and parental acceptability of gNBS using WGS. Researchers enrolled 1,000 newborns whose parents provided informed consent for both standard and genomic screening. Recruitment occurred during late pregnancy or within two weeks after birth in public and private hospitals. Information was provided through healthcare professionals, social media, and a digital decision-support tool.
Genetic material was extracted from dried blood spots (DBS) after standard NBS (stdNBS), and sequencing to a mean coverage depth of 30×. Data were analyzed by focusing on 605 genes linked to early-onset, treatable disorders. Only pathogenic or likely pathogenic variants consistent with inheritance patterns were reported; carrier or uncertain variants were excluded. Results were categorized as high-chance or low-chance, using stringent criteria to avoid false positives, with genetic counseling provided for the former.
Crucially, reprocessing of DBS samples was undertaken when required, a step that prevented two missed diagnoses, including a life-threatening UNC13D immune disorder. Parents also completed surveys and optional interviews to assess attitudes, anxiety, and decisional regret. Quantitative data were analyzed using standard statistical methods, while qualitative interviews were coded and analyzed thematically.
Key Findings
Out of 1,288 parents who expressed interest, 1,000 newborns were enrolled in the study, with slightly higher participation among older, urban, and well-educated parents. Recruitment through healthcare professionals yielded the best completion rates, while social media proved a useful supplementary method.
Sequencing from DBS cards proved feasible: although 3.2% of samples required reprocessing due to sample-related issues, procedural improvements raised on-time reporting to 81% by reducing sequencing failures. The authors emphasized that choosing not to reprocess would have resulted in missed actionable findings, underscoring the need for rigorous sample handling in gNBS.
Of the 1,000 newborns tested, 16 (1.6%) had high-chance genetic results, all confirmed through follow-up testing. These findings led to diverse clinical actions, from preventive care and monitoring to immediate treatment interventions, such as managing metabolic risk during surgery or early bone marrow transplantation for immune disorders.
Importantly, standard NBS detected only one of these 16 cases, highlighting the added value of genomic screening. Testing of family members identified 20 additional diagnoses through cascade testing, expanding clinical benefits beyond the newborns.
Parental feedback indicated high satisfaction: most parents found decision-making easy, reported low anxiety and regret, with a median decision regret score of 0, and strongly supported the expansion of gNBS. Over 99% believed it should be available to all families, and 97% supported public funding, demonstrating broad acceptance and the feasibility of integrating genomic screening into routine newborn care.
Conclusions
The BabyScreen+ study demonstrated that gNBS can effectively identify a broader range of severe, treatable childhood conditions than stdNBS, detecting 1.6% of infants with actionable genetic variants. The program proved feasible and acceptable, integrating genomic sequencing into existing healthcare systems with rapid result turnaround and minimal disruption. Parents overwhelmingly supported gNBS, showing low anxiety and decisional regret.
Strengths of the study include its clinically accredited sequencing, use of DBS, efficient automation, and multidisciplinary evaluation, all contributing to reliable and timely results. However, the authors noted that over half of cases still required manual expert review, meaning the current workflow is not yet fully scalable and will require further automation without compromising accuracy.
Limitations included the small cohort size, short study duration, and overrepresentation of highly educated participants, which may limit generalizability. Scaling the program nationwide would require significant infrastructure and workforce investment, along with evaluation of equity and access across diverse populations.
Overall, BabyScreen+ provides strong evidence that gNBS is feasible, acceptable, and clinically valuable, but further large-scale and long-term studies are needed to evaluate equity, cost-effectiveness, and sustainability.
Journal reference:
- Lunke, S., Downie, L., Caruana, J., Kugenthiran, N., De Fazio, P., Hollizeck, S., Bouffler, S. E., Amor, D. J., Archibald, A. D., Bombard, Y., Christodoulou, J., Clausen, M., Fagan, W., Gaff, C., Greaves, R. F., Gyngell, C., Kanga-Parabia, A., Lang, N., Lee, C., Lynch, F., Marty, A., Marty, M., McGregor, C., Riseley, J., Sadedin, S., Scarff, K., da Cunha Torres, M., Tutty, E., Vang, C., Wall, M., Wong, E. M., Yeung, A., Goranitis, I., Best, S., Vears, D. F., & Stark, Z. (2025). Feasibility, acceptability and clinical outcomes of the BabyScreen+ genomic newborn screening study. Nature Medicine. DOI: 10.1038/s41591-025-03986-z, https://www.nature.com/articles/s41591-025-03986-z