NRXN1 haploinsufficiency converges on RNA processing during cortical development, with partial transcriptomic concordance in adult autism cortex.

BACKGROUNDNRXN1 deletions are recurrent genetic risk factors for autism spectrum disorder (ASD), yet most functional work has focused on synaptic mechanisms. We asked whether NRXN1 haploinsufficiency is also associated with earlier gene-regulatory programs during cortical development, and whether related signals are detectable in adult ASD cortex.

METHODSWe reanalyzed two public single-cell datasets: matched control and NRXN1-heterozygous cortical organoid samples (GSE228315; 215,442 cells, 26 samples) and post-mortem adult ASD cortex (Velmeshev et al., 2019; 104,559 nuclei, 31 donors). All comparisons were performed at the sample or donor level.

RESULTSIn adult ASD cortex, donor-level analyses revealed no significant cell-type composition or CellRank-based fate-commitment differences. In organoids, paired pseudobulk comparisons identified 282 genes consistently downregulated across three or more neural cell types in NRXN1-heterozygous samples (10.6-fold enrichment, permutation p < 0.001). Robustness analyses-leave-one-gene-out, threshold-sensitivity, threshold-free consistency scoring, and unbiased GO/Reactome enrichment-supported a broad RNA-processing signal, with mRNA nuclear export and splicing prominently affected (Reactome "Metabolism of RNA" FDR = 3 × 10-10). In the same adult cohort, 8 of 16 cell types showed directional concordance under unmatched tests, but none exceeded an expression-matched permutation null after correction (0/16).

CONCLUSIONSNRXN1 haploinsufficiency is associated with coordinated downregulation of RNA-processing genes in cortical organoids. Cross-dataset concordance with adult ASD cortex is directional but not specific to NRXN1, and the convergence on mRNA nuclear export and RNA-processing genes should be interpreted cautiously and verified by direct experimental perturbation.