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

Understanding how chromosome 21 gene dosage contributes to neurodevelopmental and systemic phenotypes in trisomy 21 (T21) remains a fundamental challenge. We performed transcriptome-wide RNA sequencing on fetal cortical and hippocampal tissues from 20 T21 cases and 27 euploid controls collected between 13-22 weeks post-conception, a critical period for human brain development. Differential expression analysis revealed 572 dysregulated genes in the prefrontal cortex and 519 in the hippocampus (FDR < 5%), with significant enrichment for chromosome 21 genes. Functional enrichment analyses highlighted disruptions in neurodevelopmental, synaptic, and immune-related pathways. Among the most strongly dysregulated genes was ADARB1, a chromosome 21-encoded RNA editing enzyme, whose overexpression in T21 fetal brain was associated with increased adenosine-to-inosine (A-to-I) editing, including recoding sites in GRIA2 (p.R764G), GRIA3 (p.R775G), and GRIK2 (p.Y571C, p.Q621R). A meta-analysis incorporating nine independent transcriptomic datasets spanning early embryonic and progenitor cell types validated robust chromosome 21 dosage effects, including consistent ADARB1 overexpression. Extending these findings, a meta-analysis of A-to-I editing across datasets revealed widespread over-editing at 3'UTRs and at GRIA3 (p.R775G), a site critical for AMPA receptor desensitization. Together, these results implicate dysregulated RNA editing driven by ADARB1 overexpression as a post-transcriptional mechanism contributing to fetal neuropathology in T21 and provide a framework for understanding the broader molecular consequences of chromosome 21 dosage sensitivity during brain development.