Combining gene and biomarker screening for newborn health

For more than six decades, biomarker-based newborn screening has played a pivotal role in reducing infant mortality and long-term disability by enabling early detection of metabolic and endocrine disorders. However, traditional dried blood spot testing remains vulnerable to variations in sample quality, environmental factors, maternal health status, and technical constraints, which may result in false-positive findings or missed diagnoses. Meanwhile, next-generation sequencing has demonstrated strong diagnostic performance in critically ill infants, yet challenges remain in variant interpretation, structural variant detection, cost control, and ethical management. These limitations underscore the need for a standardized model that effectively integrates biochemical and genomic screening approaches.

Published (DOI: 10.1007/s12519-025-00996-2) on December 26, 2025, in World Journal of Pediatrics, the consensus was developed by the Newborn Inherited Metabolic Disease Screening Group and multidisciplinary experts from leading institutions across China, including Zhejiang University School of Medicine and major national pediatric centers. The document represents the first nationally structured guidance on combined screening of genes and biomarkers for neonatal diseases. It offers operational recommendations spanning informed consent, sample collection, sequencing protocols, quality control, result interpretation, and follow-up management.

The consensus establishes clear, operational criteria for disease and gene selection. Target conditions must demonstrate reliable biomarkers, clear gene-disease associations, early onset—typically before five years of age—effective therapeutic options, and favorable cost-benefit ratios. Based on these criteria, experts identified 154 disease-causing genes covering 67 inherited metabolic disorders, including amino acid metabolism disorders, organic acidemias, fatty acid β-oxidation disorders, urea cycle disorders, lysosomal storage diseases, and selected endocrine and immunological conditions.

Technically, the framework recommends integrating dried blood spot biomarker analysis with next-generation sequencing-based targeted capture panels. Sequencing coverage should exceed 300× to ensure high analytical sensitivity. Complex genomic regions, such as CYP21A2 and SLC25A13, require supplementary validation using long-read sequencing, MLPA, or Sanger confirmation. Both biomarker and genetic findings should be reported within 15 working days to support timely clinical decisions.

The consensus also outlines structured interpretation algorithms. Positive combined results require confirmation through family verification or additional diagnostic testing. Special scenarios—including heterozygous variants in autosomal recessive disorders and variants of uncertain significance—are addressed through detailed follow-up recommendations. By combining biochemical and genomic data, the dual approach enhances diagnostic accuracy and reduces delays in initiating life-saving treatment.

"Screening expansion must be guided by clinical actionability and public health feasibility," the expert panel noted. "More diseases do not necessarily translate into better outcomes." The authors emphasize that genetic testing should complement rather than replace established biomarker-based programs. Integrating genomic technologies into existing screening infrastructures ensures cost-effectiveness while maintaining ethical safeguards. Interdisciplinary collaboration, continuous quality control, and standardized reporting systems are essential to maximize clinical benefit and protect newborns and families.

If effectively implemented, combined gene-biomarker screening could substantially reduce diagnostic uncertainty and prevent irreversible complications such as neurological damage in affected infants. The framework provides a scalable roadmap for incorporating genomic technologies into national newborn screening systems without compromising efficiency. Beyond China, the model offers valuable guidance for countries exploring genomic expansion of public health screening. Future efforts will focus on optimizing data interpretation, refining cost models, and building standardized national platforms. Ultimately, integrating genomics with established screening programs may redefine neonatal preventive medicine and advance health equity worldwide.