Trisomy 21 drives ADARB1 overexpression and premature RNA recoding in the developing fetal brain

ABSTRACT: 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 13–22weeks post-conception—a critical period for human brain development. Differential expression analysis revealed 572 dysregulated genes in the 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 key recoding events 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 novel 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301886 | GEO | 2026/04/08

REPOSITORIES: GEO