Combining Gene and Biomarker Screening in Newborns: Consensus-Based Operational Overview

A multidisciplinary expert consensus outlines an operational model for combined gene–biomarker newborn screening that pairs next-generation sequencing (NGS) with dried blood spot biomarker testing within established newborn screening programs.

In the report's framing, the two modalities are complementary: biochemical markers serve as a long-standing front-line screen, while genomic data add diagnostic clarification when interpreted in a structured workflow. The report also notes that implementing an integrated pathway would require coordinated work across multidisciplinary clinical and laboratory teams, given that positive screens can prompt follow-up management. The consensus centers on the operational elements of this integrated approach.

The report places the proposal in the context of dried blood spot biomarker screening’s decades-long role in reducing infant mortality and long-term disability through early detection of metabolic and endocrine disorders. It also highlights vulnerabilities that can affect biochemical results, including variation in sample quality and external influences such as environmental factors and maternal health status, alongside technical constraints that may contribute to false-positive findings or missed diagnoses. NGS is presented as having shown strong diagnostic performance in critically ill infants, while the report also lists challenges that can limit routine use at scale, including variant interpretation, detection of structural variants, cost control, and ethical management. Against this backdrop, the combined model is described as a standardized response to these complementary strengths and limitations.

For deciding what belongs in a combined screening panel, the consensus authors describe operational selection criteria centered on clinical and program feasibility, including reliable biomarkers, clear gene–disease associations, early onset (typically before 5 years of age), effective therapeutic options, and favorable cost–benefit considerations. Using these criteria, the authors report a prioritized list spanning 154 disease-causing genes covering 67 inherited metabolic disorders, with examples including amino acid metabolism disorders, organic acidemias, fatty acid β-oxidation disorders, urea cycle disorders, and lysosomal storage diseases. This selection approach aims to focus integrated screening on conditions considered suitable for paired biochemical and genetic assessment.

On the laboratory side, the framework recommends integrating dried blood spot biomarker analysis with NGS-based targeted capture panels rather than untargeted sequencing. It specifies a sequencing coverage threshold exceeding 300× as a program standard and highlights supplementary validation methods for complex genomic regions where routine short-read workflows may be insufficient. The report lists long-read sequencing, multiplex ligation-dependent probe amplification (MLPA), and Sanger confirmation as confirmatory approaches for such regions. These technical standards are presented as supporting results that are interpretable and verifiable within the proposed integrated workflow.

The consensus also outlines structured interpretation and confirmation algorithms, specifying that both biomarker and genetic findings are intended to be reported within 15 working days to support timely clinical decisions. For positive combined results, the workflow described includes confirmation steps such as family verification or additional diagnostic testing, and it notes that special scenarios (including heterozygous variants in autosomal recessive conditions and variants of uncertain significance) are addressed through follow-up recommendations.

Overall, the consensus is presented as an operational blueprint that centers on coordinated follow-up after positive integrated screens.

Key Takeaways:

• An expert consensus proposes an integrated newborn screening workflow that combines dried blood spot biomarkers with targeted genomic testing in a complementary model.
• Disease and gene selection is described as being guided by feasibility and actionability concepts, aligning combined testing with conditions that have defined markers and gene–disease relationships.
• Operational recommendations emphasize standardized sequencing/confirmation practices, structured interpretation, and cross-disciplinary coordination around follow-up processes.