Trisomy 21 Drives ADARB1 Overexpression and Premature RNA Recoding in the Developing Fetal Brain.

Understanding how chromosome 21 gene dosage contributes to neurodevelopmental phenotypes in trisomy 21 (T21) remains a fundamental challenge. Here, we perform transcriptome-wide RNA-sequencing of fetal cortical and hippocampal tissues from T21 cases and euploid controls collected during mid-gestation, a critical window for human brain development. We identify widespread gene expression dysregulation with significant enrichment for chromosome 21 genes and perturbation of neurodevelopmental, synaptic, and immune-related pathways. Among the most strongly dysregulated genes is ADARB1, a chromosome 21-encoded RNA editing enzyme, whose overexpression associates with increased adenosine-to-inosine RNA editing, with consistent over-editing at functionally important recoding sites in glutamate and GABA receptor-related genes, including GRIK2, GRIA2, GRIA3, and GABRA3, across cortex and hippocampus. Meta-analyses across independent transcriptomic datasets validate robust chromosome 21 dosage effects, including ADARB1 overexpression and over-editing at 3'UTRs and GRIA3. These findings implicate dysregulated RNA editing as a post-transcriptional mechanism contributing to fetal neuropathology in T21.