Chd8 autism

BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice...

Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8 haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact of Chd8 haploinsufficiency on maternal-offspring interactions. While differences in maternal care as a function of Chd8 genotype have not been studied directly, a previous study showed that pup survival was reduced when reared by Chd8 heterozygous dams compared with wild-type (WT) dams, suggesting altered maternal care as a function of Chd8 genotype...

Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD's genetic susceptibility is imparted by de novo mutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes - CHD8 and SCN2A and used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons and cerebral forebrain organoids to correct the effects of haploinsufficiency, taking advantage of the presence of a wildtype allele of each gene and endogenous gene regulation...

CHD8 is a high penetrance, high confidence risk gene for autism spectrum disorder (ASD), a neurodevelopmental disorder that is substantially more prevalent among males than among females. Recent studies have demonstrated variable sex differences in the behaviors and synaptic phenotypes of mice carrying different heterozygous ASD-associated mutations in Chd8 . We examined functional and structural cellular phenotypes linked to synaptic transmission in deep layer pyramidal neurons of the prefrontal cortex in male and female mice carrying a heterozygous, loss-of-function Chd8 mutation in the C57BL/6J strain across development from postnatal day 2 to adulthood...

Chromodomain helicase DNA binding domain (CHD) proteins, including CHD7 and CHD8, remodel chromatin to enable transcriptional programs. Both proteins are important for proper neural development as heterozygous mutations in Chd7 and Chd8 are causative for CHARGE syndrome and correlated with autism spectrum disorders, respectively. Their roles in mature neurons are poorly understood despite influencing the expression of genes required for cell adhesion, neurotransmission, and synaptic plasticity. The Drosophila homolog of CHD7 and CHD8, Kismet (Kis), promotes neurotransmission, endocytosis, and larval locomotion...

BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems...

CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior...

BACKGROUND: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder. Unique ASD subtypes have been proposed based on specific genotype-phenotype combinations. The ASD subtype associated with various chromodomain helicase DNA-binding protein 8 (CHD8) mutations has been associated with an incidence of autistic regression greater than that of all-cause ASD, but the mean age of onset of this subtype remains unknown. METHODS: Here we describe a patient with a known de novo CHD8 gene mutation (heterozygous c...

Heterozygous, de novo, loss-of-function variants of the CHD8 gene are associated with a high penetrance of autism and other neurodevelopmental phenotypes. Identifying the neurodevelopmental functions of high-confidence autism risk genes like CHD8 may improve our understanding of the neurodevelopmental mechanisms that underlie autism spectrum disorders. Over the last decade, a complex picture of pleiotropic CHD8 functions and mechanisms of action has emerged. Multiple brain and non-brain cell types and progenitors appear to be affected by CHD8 haploinsufficiency...

Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia and the failure of meiotic double-strand break (DSB) formation, leading to meiotic prophase I arrest and cell death...

The chromodomain helicase DNA-binding protein 8 (CHD8) is a chromatin remodeler whose mutation is associated, with high penetrance, with autism. Individuals with CHD8 mutations share common symptoms such as autistic behaviour, cognitive impairment, schizophrenia comorbidity, and phenotypic features such as macrocephaly and facial defects. Chd8 -deficient mouse models recapitulate most of the phenotypes seen in the brain and other organs of humans. It is known that CHD8 regulates - directly and indirectly - neuronal, autism spectrum disorder (ASDs)-associated genes and long non-coding RNAs (lncRNAs) genes, which, in turn, regulate fundamental aspects of neuronal differentiation and brain development and function...

About 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of ∼1000 genes that may be involved. The new challenge now is to investigate the molecular and cellular functions of these genes during neural and brain development, and then even more challenging, to link the altered molecular and cellular phenotypes to the ASD clinical manifestations. In this study, we use single cell RNA-seq analysis to study one of the top risk gene, CHD8 , in cerebral organoids, which models early neural development...

Whole-exome sequencing of autism spectrum disorder (ASD) probands and unaffected family members has identified many genes harboring de novo variants suspected to play a causal role in the disorder. Of these, chromodomain helicase DNA-binding protein 8 (CHD8) is the most recurrently mutated. Despite the prevalence of CHD8 mutations, we have little insight into how CHD8 loss affects genome organization or the functional consequences of these molecular alterations in neurons. Here, we engineered two isogenic human embryonic stem cell lines with CHD8 loss-of-function mutations and characterized differences in differentiated human cortical neurons...

Autism is a neurodevelopmental disorder characterized by early-onset social behavioral deficits and repetitive behaviors. Chromodomain helicase DNA-binding protein (CHD8) is among the genes most strongly associated with autism. In addition to the core behavioral symptoms of autism, affected individuals frequently present with gastrointestinal symptoms that are also common among individuals harboring mutations in the gene encoding CHD8. However, little is known regarding the mechanisms whereby CHD8 affects gut function...

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...

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...