chd8

Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged; multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome respectively; variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome; variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth; while very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder...

The dorsolateral prefrontal cortex (dlPFC) is a derived cortical area in primates that is involved in myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, we performed Patch-seq and single-nucleus multiomic analyses of the rhesus macaque dlPFC to identify genes governing neuronal maturation during midfetal to late-fetal development. Our multimodal analyses have identified genes and pathways important for the maturation of distinct neuronal populations as well as genes underlying the maturation of specific electrophysiological properties...

Gene ontology analyses of high-confidence autism spectrum disorder (ASD) risk genes highlight chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional work in vivo has additionally implicated tubulin biology and cellular proliferation. As many chromatin regulators, including ASD risk genes ADNP and CHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ, and KMT5B) specifically with respect to tubulin biology...

CHD8 encodes chromodomain helicase DNA-binding protein 8 and its mutation is a highly penetrant risk factor for autism spectrum disorder (ASD). CHD8 serves as a key transcriptional regulator on the basis of its chromatin-remodeling activity and thereby controls the proliferation and differentiation of neural progenitor cells. However, the function of CHD8 in postmitotic neurons and the adult brain has remained unclear. Here we show that Chd8 homozygous deletion in mouse postmitotic neurons results in downregulation of the expression of neuronal genes as well as alters the expression of activity-dependent genes induced by KCl-mediated neuronal depolarization...

Severe asthma imposes a physical and economic burden on both patients and society. As chromatin regulators (CRs) influence the progression of multiple diseases through epigenetic mechanisms, we aimed to study the role of CRs in patients with severe asthma. Transcriptome data (GSE143303) from 47 patients with severe asthma and 13 healthy participants was downloaded from the Gene Expression Omnibus database. Enrichment analysis was performed to investigate the functions of differentially expressed CRs between the groups...

CHD8 mutation is a case of genetic related autism spectrum disorder(ASD), In our research, We describe here the derivation of the iPSC line SDQLCHi051-A from a patient with autism spectrum disorder (ASD) due to two heterozygote mutations (c.6728G > A and c.3876 T > G) in the CHD8 gene. The resulting iPSC line has typical iPSCs characteristics, including pluripotency and trilineage differentiation hallmarks.

We aimed to identify unique constellations of sensory phenotypes for genetic etiologies associated with diagnoses of autism spectrum disorder (ASD) and intellectual disability (ID). Caregivers reported on sensory behaviors via the Sensory Profile for 290 participants (younger than 25 years of age) with ASD and/or ID diagnoses, of which ~ 70% have a known pathogenic genetic etiology. Caregivers endorsed poor registration (i.e., high sensory threshold, passive behaviors) for all genetic subgroups relative to an "idiopathic" comparison group with an ASD diagnosis and without a known genetic etiology...

The presence of large genomic rearrangements (LGRs) has been heavily investigated in breast and ovarian cancer. However, correlations between LGRs and cancer types beyond these two have not been extensively profiled, likely due to the highly inefficient methods of detecting these types of alterations. This study utilized next-generation sequencing (NGS) to analyze and classify the germline LGR profile in 17,025 cancer patients across 22 cancer types. We characterized newly identified LGRs based on predicted pathogenicity and took a closer look at genes that acquire both germline and somatic mutations within our samples...

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Chd8+/N2373K mice with a human C-terminal-truncating mutation (N2373K) display autistic-like behaviors in juvenile and adult males but not in females. In contrast, Chd8+/S62X mice with a human N-terminal-truncating mutation (S62X) display behavioral deficits in juvenile males (not females) and adult males and females, indicative of age-differential sexually dimorphic behaviors. Excitatory synaptic transmission is suppressed and enhanced in male and female Chd8+/S62X juveniles, respectively, but similarly enhanced in adult male and female mutants...

The cerebellum contains most of the neurons in the human brain, and exhibits unique modes of development, malformation, and aging. For example, granule cells-the most abundant neuron type-develop unusually late and exhibit unique nuclear morphology. Here, by developing our high-resolution single-cell 3D genome assay Dip-C into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we were able to resolve the first 3D genome structures of single cerebellar cells, create life-spanning 3D genome atlases for both human and mouse, and jointly measure transcriptome and chromatin accessibility during development...

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS ( AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1 )...

The commensal microbiota regulates the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) in bone marrow. Whether and how the microbiota influences HSPC development during embryogenesis is unclear. Using gnotobiotic zebrafish, we show that the microbiota is necessary for HSPC development and differentiation. Individual bacterial strains differentially affect HSPC formation, independent of their effects on myeloid cells. Early-life dysbiosis in chd8-/- zebrafish impairs HSPC development...

Preclinical models of neurodevelopmental disorders typically use single inbred mouse strains, which fail to capture the genetic diversity and symptom heterogeneity that is common clinically. We tested whether modeling genetic background diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, CHD8. We measured clinically relevant phenotypes in >1,000 mice from 33 strains, including brain and body weights and cognition, activity, anxiety, and social behaviors, using 5 behavioral assays: cued fear conditioning, open field tests in dark and bright light, direct social interaction, and social dominance...

The CHD8 mutation was initially identified as the cause of autism spectrum disorder (ASD) and was previously marked as Autism, susceptibility to, 18 [MIM 615032] on Online Mendelian Inheritance in Man (OMIM). As many patients with CHD8 mutation showed other characteristics along with autism, the phenotype was relabeled as intellectual developmental disorder with autism and macrocephaly (IDDAM) in May 2022. We report a 3-year 10-month-old boy who presented with overgrowth, intellectual disability, dysmorphic facial features, and ASD...

The chromodomain helicase DNA-binding protein CHD8 is the most frequently mutated gene in autism spectrum disorder. Despite its prominent disease involvement, little is known about its molecular function in the human brain. CHD8 is a chromatin regulator which binds to the promoters of actively transcribed genes through genomic targeting mechanisms which have yet to be fully defined. By generating a conditional loss-of-function and an endogenously tagged allele in human pluripotent stem cells, we investigated the molecular function and the interaction of CHD8 with chromatin in human neurons...

Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 462 genes implicated in 'regulation of RNA splicing' and 'mRNA catabolic process'...

Autism spectrum disorders (ASD) are ~4-times more common in males than females, and CHD8 (a chromatin remodeler)-related ASD shows a strong male bias (~4:1), although the underlying mechanism remains unclear. Chd8 -mutant mice with a C-terminal protein-truncating mutation (N2373K) display male-preponderant behavioral deficits as juveniles and adults, although whether this also applies to other Chd8 mutations remains unknown. In addition, it remains unclear whether sexually dimorphic phenotypes in Chd8 -mutant mice are differentially observed in males and females across different ages...

Individuals with mutations in CHD8 present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, using a stable constitutive chd8 mutant zebrafish model, we found that the loss of chd8 leads to a reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube, and that their early migration capability was altered. At later stages, although the intestinal colonization by NCCs was complete, we found the decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in the absence of chd8 Furthermore, transcriptomic analyses revealed an altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways...

BACKGROUND: Neurodevelopmental disorders are genetically heterogeneous pediatric conditions. The first tier diagnostic method for uncovering copy number variations (CNVs), one of the most common genetic etiologies in affected individuals, is chromosomal microarray (CMA). However, this methodology is not yet a routine molecular cytogenetic test in many parts of the world, including Hungary. Here we report clinical and genetic data of the first, relatively large Hungarian cohort of patients whose genetic testing included CMA...