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

Autism-associated NRXN1α deletion rewires the H3K27me3 landscape and epigenetically disrupts human neural induction

Findings indicate that NRXN1α deletion disrupts neural lineage commitment through a multi-layered disruption involving spliceosome dysregulation of chromatin regulatory genes, H3K27me3 redistribution at developmental promoters, and chromatin-level priming into non-neural fates.

Integrative functional genomics maps synaptic and developmental-regulatory autism risk-gene sets across human cortex

Analysis of haploinsufficiency in human neural progenitor cells: insights into early molecular effects of autism-related genes.

Haploinsufficiency describes a phenomenon where one functional allele of a gene in a diploid cell or organism is insufficient for a normal phenotype. There are several neurodevelopmental disorders (NDD) affected by the haploinsufficiency phenomenon, and many of them are related to autism spectrum disorder (ASD). Here, we aim to identify genes involved in the early stages of neural differentiation when one of the two alleles is lost. We thus differentiated a genome-wide heterozygous loss-of-function CRISPR library into neural progenitor cells (NPCs) and defined about 250 genes essential for neural differentiation in a haploinsufficient manner. We were able to identify NDD-related dosage-sensitive pathways and pinpoint specific molecular processes affected by ASD-related genes. By comparing the molecular phenotypes of homozygote and heterozygote mutations, we could illuminate overlapping and distinct transcriptional pathways affected in the two mutant models, along with partial chemical rescue of some of these phenotypes. Our work provides a comprehensive framework for exploring dosage-sensitive regulation in early neural development and offers new insights into the embryonic molecular basis of ASD and other NDDs driven by gene dosage imbalance.

16p11.2 microdeletion enhances gene expression variability between human IPSC-derived forebrain interneuron progenitor cells in culture

The 574-kilobase pair 16p11.2 microdeletion raises a person’s odds for neurodevelopmental and energy balance conditions, particularly autism and obesity, with considerable clinical heterogeneity, and how much this reflects genetic versus environmental or stochastic factors is unclear. GABAergic forebrain interneurons originate from progenitors residing in the ventricular zones of the fetal ventral telencephalon, and their perturbation is implicated in 16p11.2 phenotypes, prompting investigation of how the 16p11.2 microdeletion impacts their development. Here we studied human-induced pluripotent stem cell (IPSC) derived ventral telencephalic interneuron progenitors in two-dimensional culture, comparing IPSCs isogenic except for a heterozygous 16p11.2 microdeletion to minimize confounding effects of genetic background. Single-cell RNA sequencing generated single-cell transcriptome populations for comparative bioinformatics, revealing hundreds of differentially expressed transcripts, many associated with cell signaling, chromatin biology, and neurodevelopmental conditions. Pertinently, we find that transcript level variation is significantly greater between 16p11.2 heterozygous progenitors than their isogenic wild type counterparts both for sets of genes comprising regulons, gene-sets functionally connected by transcription factor regulation, and for randomly selected gene sets. This indicates that the 16p11.2 locus itself has a genome-wide property in stabilizing transcription between cells. Regulons with the greatest increased variability in 16p11.2 heterozygous progenitors exhibit strong enrichment for cell cycle-related genes, and many are regulated by transcription factors themselves associated with autism and/or obesity, suggesting the hypothesis that enhanced transcriptional variation contributes to 16p11.2 microdeletion phenotypes.

Mapping lncRNAs onto multilevel mRNA co‑expression modules in autism.

Autism spectrum disorder (ASD) involves heterogeneous genetic and transcriptomic alterations, but how these changes are organized across hierarchical co-expression scales and linked to long noncoding RNAs (lncRNAs) remains incompletely understood. Here, we present Minimum Span Clustering Network (MSCN), an unsupervised, deterministic framework that constructs traceable multilevel mRNA co-expression hierarchies without requiring soft-thresholding powers, fixed module numbers, cut heights, or stochastic initialization. Applied to two independent ASD brain transcriptome cohorts, MSCN reveals hierarchical gene modules across four resolution levels, enabling the detection of transcriptional patterns ranging from low-level, specific signals to high-level, broader biological pathways. We uncovered modules enriched in neuronal/axonal, developmental, and immune-related pathways, reflecting interconnected neurodevelopmental and immune-dysregulation programs in ASD. Cross-method comparisons showed that MSCN complements WGCNA and MEGENA by preserving biologically concordant modules while providing an explicit parent-child hierarchy; simulation and benchmark analyses supported comparable module recovery, preservation, and enrichment performance. By mapping lncRNAs to MSCN-derived mRNA modules, we identified lncRNAs associated with ASD-related mRNA modules and evaluated them as candidate statistical mediators in downstream transcription factor (TF)-lncRNA-mRNA analyses. This analysis identified over 11,000 candidate TF-lncRNA-mRNA axes, including 644 axes involving 46 SFARI score 1 or 2 genes, four of which were syndromic genes, and 12 named lncRNA mediators. External transcriptomic evaluation further supported 789 axes, including representative HIF1A-STXBP5-AS1-CADPS, E2F1-PART1-SCN2A, and RELA-RFPL1S-GRIN2A relationships. Together, these findings establish MSCN as a scalable framework for decomposing ASD mRNA co-expression architecture, provide a hypothesis-generating resource linking coding and noncoding transcriptomic alterations, and help prioritize these relationships for future validation.

Transcriptomic Convergence in Autism Spectrum Disorder: Synaptic, Immune‐Glial and RNA‐Regulatory Axes in the Human Cerebral Cortex

Autism spectrum disorder (ASD) arises from highly heterogeneous genetic and developmental liabilities, raising the question of whether this heterogeneity converges on shared molecular programmes in the human cerebral cortex. This structured review, based on systematic database searching and narrative synthesis, examined that question specifically in human post‐mortem cortical transcriptomic studies. PubMed, Scopus and Europe PMC were searched from 1 January 2009 to 6 May 2026, and 43 studies met the final eligibility criteria. Across the available literature, the evidence does not support a single invariant cortical transcriptomic signature in ASD. Rather, the most consistent signal indicates non‐uniform convergence on reduced neuronal and synaptic expression together with increased immune‐glial programmes. A substantial additional body of evidence implicates dysregulation of transcript‐regulatory processes, particularly in studies interrogating alternative splicing and related RNA‐processing mechanisms. Cell‐resolved datasets further suggest that these abnormalities are concentrated within defined neuronal and glial populations rather than being distributed uniformly across the cortex. By contrast, mitochondrial and broader metabolic alterations are supported less consistently and are better interpreted as conditional or secondary features of cortical pathology than as equally well‐established core axes. Interpretation of these findings is constrained by the structure of the evidence base itself. Only 9 of the 43 included studies were judged to provide direct support for the central convergence question, and only 13 were based on primary independent cohorts; much of the literature relies on dataset reuse, regionally restricted sampling and heterogeneous analytical platforms. Collectively, human cortical transcriptomic studies in ASD support a model of partial, context‐dependent convergence on a limited set of biological programmes, rather than a single stable molecular lesion.