Abstract

The integration of long-read sequencing (LRS) into newborn screening (NBS) programs offers transformative 
potential for public health by enhancing diagnostic yield, resolving complex genetic variants, and providing 
expanded carrier and prenatal information. Compared to traditional short-read sequencing, LRS improves 
resolution of structural variants, splice events, and repeat expansions, facilitating earlier and more precise 
interventions. However, the expansion introduces challenges, including data privacy concerns, ethical dilemmas, 
incidental findings, equity considerations, and workforce and infrastructure requirements. Public health decision 
frameworks that systematically evaluate benefits, harms, economic implications, and stakeholder perspectives are 
essential for guiding implementation. Pilot studies, phased rollouts, and comparative effectiveness and cost
effectiveness analyses provide critical evidence for real-world application. Future research should focus on 
technological validation, data stewardship, workforce capacity, and policy alignment to ensure equitable, safe, and 
effective adoption of LRS in NBS programs.