Integrated multiomics profiling of amniotic fluid exosomes reveals dysregulated lipid and protein signatures in fetal 22q11.2 deletion syndrome

<h4>Background</h4>Amniotic fluid exosomes (AF-Exos) are pivotal carriers of biological information during fetal development; however, their role in 22q11.2 Deletion Syndrome (22q11.2DS) remains unclear. To elucidate the molecular mechanisms underlying fetal anomalies in 22q11.2DS, this study performed a comprehensive multiomics analysis of AF-Exos obtained from 22q11.2DS fetuses (n = 5) and matched controls (n = 5).<h4>Results</h4>While exosomal morphology and size distribution remained unaltered, integrated lipidomic and proteomic profiling revealed profound molecular remodeling. Lipidomics analysis revealed a specific suppression of diacylglycerols, triacylglycerols, and ceramides, accompanied by a shift in carbon chain length distribution. Concurrently, data-independent acquisition proteomics identified 329 differentially expressed proteins, highlighting a significant downregulation of PI4KA and widespread perturbations in pathways governing cardiovascular morphogenesis, angiogenesis, and SNARE-mediated vesicular transport. Integrated network analysis revealed strong correlations between the depletion of key lipids and reduced abundance of PI4KA and SNARE complex components, suggesting a potential interplay between lipid metabolism and vesicle trafficking.<h4>Conclusions</h4>These findings, extending beyond the primary genetic driver TBX1, point to distinct alterations in lipid signaling and exosomal transport machinery in 22q11.2DS, suggesting a novel parallel pathogenic mechanism. This study provides a novel multiomics resource for understanding 22q11.2DS pathogenesis and generates valuable hypothesis-driven candidates for future mechanistic investigation.