Exploratory donor-aware analysis of developmental transcriptomic trajectories in 15q13.3-deletion cortical organoids

This descriptive, hypothesis-generating study examined whether 15q13.3-deletion cortical organoids show developmental transcriptomic differences overlapping retinoic acid (RA)-related gene-expression programs. Signatures derived from early RA exposure and prolonged, 7-day all-trans RA (ATRA) treatment were evaluated in public cortical organoid data from three deletion and 17 control donors. Donors, rather than individual samples, were the units of inference; 16 controls and all three deletion donors had sufficient time points for slope testing. Early human, early mouse, and conserved early RA signatures were not significant. A broad ATRA-derived differentiation score showed a negative deletion-control slope difference (exact P = 0.0083; false-discovery rate = 0.0206), but a non-RA maturation score was also significant. The prolonged score correlated strongly with maturity. Sensitivity analyses adjusting for measured maturation and composition did not identify an RA-specific component; neither the targeted RA program nor the covariate-adjusted joint trajectory test was significant. External and single-cell analyses provided biological context, not independent validation. The findings suggest a developmental/maturation-associated trajectory difference overlapping a broad prolonged ATRA-associated program. The three-donor case group and heterogeneous source models limit stability and generalizability; the results do not establish altered RA signaling, vitamin A deficiency, or retinoid-treatment relevance.