Abstract

Sickle cell disease (SCD) is a prevalent monogenic disorder with significant morbidity and mortality worldwide, 
particularly in low- and middle-income countries. Early diagnosis through population screening is critical to 
reduce adverse health outcomes and enable timely interventions. Long-read sequencing (LRS) technologies, 
including Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT), offer substantial advantages 
over short-read approaches, providing comprehensive detection of HbS variants, structural variations, haplotype 
phasing, and mosaicism within globin gene clusters. This review evaluates the clinical validity and utility of LRS 
for SCD, emphasizing its potential for newborn and carrier screening programs, particularly in resource-limited 
settings. It discusses technical requirements, workforce training, data governance, ethical considerations, and 
health economic implications. Lessons from bench-to-population perspectives underscore the importance of tiered 
implementation strategies, infrastructure investment, and stakeholder engagement. Findings highlight that 
integrating LRS into population screening programs can enhance diagnostic accuracy, inform clinical decision
making, and support equitable access to genomic-informed care. Future research should focus on longitudinal 
monitoring, pilot implementation studies, and cost-effectiveness analyses to guide policy development and 
sustainable adoption of LRS for SCD screening globally.