Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CHD8”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

4 recordsLinked to original sources
PubMed2025

Cell-type-specific dysregulation of gene expression due to Chd8 haploinsufficiency during mouse cortical development.

Disruptive variants in the chromodomain helicase CHD8 are associated with risk for autism spectrum disorder (ASD). CHD8 haploinsufficiency is hypothesized to contribute to ASD by perturbing neurodevelopmental gene expression. However, insight into cell-type-specific transcriptional effects of CHD8 haploinsufficiency remains limited. We used single-cell and single-nucleus RNA sequencing to identify dysregulated genes in the embryonic and juvenile Chd8+/- mouse cortex. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory conserved between mouse and human developing cortex, increasing from progenitor zones to the cortical plate. Genes associated with neurodevelopmental disorders or involved in chromatin remodeling and neuron projection development were dysregulated in Chd8+/- embryonic radial glia. Genes implicated in synaptic activity and organization were dysregulated in Chd8+/- postnatal excitatory cortical neurons, suggesting impaired synaptogenesis. Our findings reveal complex patterns of transcriptional dysregulation due to Chd8 haploinsufficiency, potentially with distinct impacts on progenitors and maturing neurons in the excitatory neuronal lineage.

Animals↗
PubMed2026

De novo chromatin remodelling variants in sporadic Chiari 1 malformation.

Chiari 1 malformation (CM1) is the most common congenital malformation of the human hindbrain. Although prior studies have implicated chromatin-remodeling genes in CM1, the de novo genetic architecture and underlying neurodevelopmental mechanisms remain incompletely defined. To investigate the molecular genetics of a novel familial form of CM1 linked with syringomyelia and tethered cord and determine whether rare, damaging de novo variants (DNVs) contribute to sporadic CM1 risk with gene- and pathway-level resolution, we performed whole-exome sequencing in an ultra-rare multigenerational family with CM1 and associated spinal pathology, and in the largest assembled trio-based cohort to date, comprising 1,585 proband-parent trios with sporadic, idiopathic CM1 (2017-2025). The comparison cohort included 1,798 unaffected control siblings. Clinical phenotyping was by systematic medical record review. Structural domain mapping, in silico modeling, and integration with single-cell transcriptomic data from developing human cerebellum was conducted to assess biological plausibility. A heterozygous loss-of-function variant in CHD3 segregated with CM1 and syringomyelia in a multigenerational family. In the trio-based cohort, rare protein-altering DNVs were significantly enriched across multiple chromodomain helicase DNA-binding (CHD) genes, including CHD1, CHD3, CHD4, and CHD8, exceeding gene-specific mutation expectations (protein-damaging variants: P = 1.3 × 10-9; predicted loss-of-function variants: P = 8.6 × 10-5). CHD1 contained two pathogenic DNVs (p.A999D and p.E984K). CHD4 (p.D744N, p.T1813P, and p.I1102T) and CHD8 (p.R1402X, p.R1472X, and p.R2035X) each contained three new DNVs. Variants clustered within conserved ATPase, helicase, and chromodomain regions essential for chromatin remodeling, and these patients frequently had comorbid developmental delay and related neurodevelopmental features. Single-cell transcriptomic analyses demonstrated enrichment in Purkinje cells and inhibitory neurons of midgestational cerebellum, where CHD gene products form a coherent chromatin-regulatory network. Rare, large-effect DNVs that disrupt chromatin-remodeling programs contribute to sporadic CM1, implicating genetically encoded dysregulation of cerebellar development as a central disease mechanism. Exome sequencing may complement surgical evaluation of children with sporadic CM1, particularly when accompanied by neurodevelopmental concerns, informing prognosis and family counseling.

de novo variants↗
PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗
PubMed2026

Advancements in the Understanding of the Genetics of Obsessive-Compulsive Disorder (OCD).

PURPOSE OF REVIEW: This review summarizes recent advances in the genetics of Obsessive-Compulsive Disorder (OCD), their contribution to understanding disorder biology, and implication for clinical translation. RECENT FINDINGS: Recent GWAS identified 30 genome-wide significant loci and prioritized 25 putatively causal genes. Rare variant studies implicated specific genes, including CHD8, CELSR3, SLITRK5, and QRICH1. Evidence from common and rare variants support brain- and immune-related pathways. Genetic overlap with obsessive compulsive symptoms and other psychiatric disorders indicate shared underlying biology. Current evidence is largely based on individuals of European ancestry, although global efforts are underway to improve ancestral diversity in OCD genetics. Given the urgent need for improved treatment, genetically informed clinical translation approaches hold promise, including pharmacogenetics and drug repurposing. Recent advances in OCD genetics support a highly polygenic architecture, implicate specific neuro-biological and immune pathways, and provide new opportunities for clinical translation.

Humans↗