Multicohort analysis unveils axon guidance pathways linking small for gestational age to spirometric restriction.

Summary

Across multiple birth cohorts, about one-third of SGA newborns showed a cord-blood endotype characterized by dysregulated axon-guidance proteins. These signals inversely tracked with later spirometric restriction, and convergent support from GWAS and a sheep model linked axon-guidance genes to spirometric indices.

Key Findings

• Approximately one-third of SGA children exhibit a cord-blood molecular endotype featuring dysregulated axon-guidance proteins.
• Later-life peripheral blood levels of these proteins inversely associate with spirometric restriction.
• GWAS and an experimental sheep model provide convergent evidence linking axon-guidance genes to spirometric indices.

Clinical Implications

Identifying an axon-guidance molecular endotype in SGA infants could enable early risk stratification and surveillance for restrictive ventilatory impairment, informing preventive strategies.

Limitations

• Causality remains inferential despite genetic and animal-model triangulation.
• Generalizability beyond the included cohorts and populations requires validation.

Future Directions

Prospective validation of the axon-guidance endotype in diverse populations and interventional studies to test modifiable pathways influencing lung growth.