Related Experiment Video
Updated: Jun 30, 2026
Mapping Infant Immunity with Minimal Input: Integrative Single-Cell and Multiomic Profiling
Published on: April 3, 2026
Newborns with sickle cell trait have distinct peripheral blood molecular signatures across the first week of life
Abhinav K Checkervarty1,2,3, Casey P Shannon1,2, Travis M Blimkie4,5
1PROOF (Prevention of Organ Failure) Centre of Excellence, Providence Research, Providence Health Care, Vancouver, BC, Canada.
Insights
Sickle cell trait (SCT) in newborns shows molecular immune changes within the first week of life, even without obvious symptoms. Understanding these early signatures may help predict future health risks and develop preventive strategies for sickle cell disorders.
Area of Science:
- Genetics and immunology
- Molecular biology
- Neonatal research
Background:
- Sickle cell trait (SCT) is a heterozygous HBB gene mutation, often asymptomatic but can cause complications.
- Understanding SCT's impact on the immune system is crucial for preventing clinical issues.
- West Africa has a high prevalence of sickle cell disorders.
Purpose of the Study:
- To identify newborns with SCT in The Gambia using RNA-sequencing.
- To investigate early immune development and molecular signatures associated with SCT in newborns.
- To explore potential links between SCT and other health conditions.
Main Methods:
- Genotyping 720 newborns from The Gambia for SCT and sickle cell disease (SCD) using RNA-sequencing.
- Analyzing molecular signatures and immune development in SCT newborns across the first week of life.
- Validating findings in an independent cohort of 45 neonates.
Main Results:
- Identified 17% of newborns with SCT and 0.6% with SCD.
- Newborns with SCT exhibited distinct molecular signatures, including reduced plasma proteins by day 3.
- Observed enrichment of pathways linked to SCD, hematologic, hepatic, and renal disorders.
Conclusions:
- SCT is associated with molecular immune changes detectable within the first week of life.
- These early molecular alterations may indicate future disease risks.
- Monitoring SCT-associated changes can inform preventive strategies for sickle cell disorders.
Abstract:
Sickle cell trait (SCT) is a genetic condition characterized by a heterozygous A-T substitution (Glu to Val) in 1 copy of the β-globin (HBB) gene on chromosome 11. Although often asymptomatic, individuals with SCT can experience complications under stress, such as hypoxia, dehydration, and extreme exertion, leading to vaso-occlusion, organ damage, and impaired immune defenses. Understanding the impact of SCT on the immune system may aid in preventing clinical complications. We genotyped 720 newborns from The Gambia, West Africa, an area in which people are prone to have sickle cell disorders, using RNA-sequencing reads mapped to the HBB gene to identify those with SCT and investigate immune development using single-omics and multiomics approaches. We identified 118 newborns (~17%) with SCT and 4 (0.6%) with sickle cell disease (SCD). Newborns with SCT demonstrated distinct molecular signatures across day of life (DOL) 0, 1, 3, and 7, compared with those without, including reduction of DOL 3 plasma proteins (eg, cysteine-rich secretory protein-3, inter-α-trypsin inhibitor 1, tetranectin, and cadherin-5). Additionally, we observed enrichment of pathways previously associated with SCD, such as the Jison sickle cell pathway, along with those linked to hematologic (chronic leukemia), hepatic (liver cancer), and renal (aging kidney) functions and disorders. These SCT-based associations were validated in an independent cohort of 45 neonates. Despite the absence of overt early clinical phenotypes, SCT-associated changes manifest in the first week of life at the molecular level. Monitoring and characterizing these associations may enable the identification of future disease risks and the development of preventive strategies. This trial was registered at www.clinicaltrials.gov as #NCT03246230.
