For more than sixty years, newborn screening using biomarkers has helped reduce infant deaths and long-term disabilities by allowing early detection of metabolic and endocrine disorders. Traditional dried blood spot testing, however, can be affected by sample quality, environmental conditions, maternal health, and technical limitations. These factors may lead to false positives or missed diagnoses. Next-generation sequencing (NGS) has shown promise in diagnosing critically ill infants but faces challenges with interpreting genetic variants, detecting structural changes in DNA, controlling costs, and managing ethical issues.
A consensus document published on December 26, 2025 in the World Journal of Pediatrics (DOI: 10.1007/s12519-025-00996-2) was developed by the Newborn Inherited Metabolic Disease Screening Group along with experts from Zhejiang University School of Medicine and other major pediatric centers across China. This document is the first nationally structured guidance for combining gene and biomarker screening in newborns. It provides operational recommendations for informed consent, sample collection, sequencing protocols, quality control measures, result interpretation, and follow-up management.
The guidelines define clear criteria for selecting diseases and genes to include in screening programs. Conditions should have reliable biomarkers, a strong link between gene mutations and disease development, early onset—usually before age five—available treatments that are effective if started early, and a favorable balance between cost and benefit. Using these standards, experts identified 154 genes responsible for 67 inherited metabolic disorders such as amino acid metabolism defects, organic acidemias, fatty acid β-oxidation disorders, urea cycle defects, lysosomal storage diseases as well as certain endocrine and immune system conditions.
Technically, the framework suggests combining traditional biomarker analysis from dried blood spots with NGS-based targeted capture panels. Sequencing coverage should be above 300× to achieve high sensitivity. Complex genomic regions like CYP21A2 and SLC25A13 need additional validation through long-read sequencing or methods such as MLPA or Sanger sequencing confirmation. Both biochemical marker results and genetic findings should be available within fifteen working days to help doctors make timely decisions.
Interpretation algorithms are also included in the consensus. If both tests show positive results for a condition, confirmation is needed through family verification or further diagnostic tests. Special cases—such as finding only one mutation in autosomal recessive diseases or discovering variants whose significance is unclear—are addressed with detailed follow-up plans. By combining both biochemical data and genetic information, this dual approach improves diagnostic accuracy and helps start treatment without delay.
"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 highlight that genetic testing should add to—not replace—current biomarker-based programs. Adding genomic technologies into existing systems can be cost-effective while upholding ethical standards. Collaboration across disciplines along with ongoing quality control checks and standardized reporting will help ensure maximum clinical benefit for newborns and their families.
If implemented effectively on a national scale in China or elsewhere, combined gene-biomarker screening could lower diagnostic uncertainty and prevent irreversible harm such as neurological damage among infants with inherited disorders. The framework offers a model that can expand public health screening programs responsibly while maintaining efficiency standards worldwide.
