Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (over
growth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.
Katayama Y, etal., Nature. 2016 Sep 7;537(7622):675-679. doi: 10.1038/nature19357.
Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours. ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently id
entified many de novo mutations in a variety of genes in individuals with ASD, with CHD8, a gene encoding a chromatin remodeller, being most frequently affected. Whether CHD8 mutations are causative for ASD and how they might establish ASD traits have remained unknown. Here we show that mice heterozygous for Chd8 mutations manifest ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but instead gave rise to small but global changes in gene expression in the mouse brain, reminiscent of those in the brains of patients with ASD. Gene set enrichment analysis revealed that neurodevelopment was delayed in the mutant mouse embryos. Furthermore, reduced expression of CHD8 was associated with abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes. REST activation was also observed in the brains of humans with ASD, and CHD8 was found to interact physically with REST in the mouse brain. Our results are thus consistent with the notion that CHD8 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis probably resulting from a delay in neurodevelopment.
Alotaibi M and Ramzan K, Discoveries (Craiova). 2020 Mar 31;8(1):e107. doi: 10.15190/d.2020.4.
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, usually diagnosed in early childhood, that are characterized by adaptive deficits in social interaction, communication skills, and restricted or stereotyped repetitive patterns of behavior. There had been limite
d success to define ASD subtypes on the behavioral basis. Genetically categorized ASD subtypes may provide basis to determine the course, prognosis, and individualized mechanism based treatment. Mutations in chromodomain helicase DNA-binding protein 8 (CHD8) gene, have been associated with autism, macrocephaly, speech delay, distinct facial features, sleep and gastrointestinal disturbances. There are few cases in the literature reporting de novo mutations of CHD8 exhibiting sporadic ASD. Here we describe a Saudi boy with developmental delay, intellectual disability, macrocephaly, craniofacial abnormalities, speech delay, but without any history of seizures, gastrointestinal problems or sleep disturbance. Whole exome sequencing for parent-child trio revealed a de novo heterozygous loss-of-function mutation (c.4984C>T, p.Arg1662Ter) in CHD8 gene. Our findings elaborate the genotype-phenotype correlation and confirm that the CHD8 disruptions represent a clinical ASD subtype and further highlight the significance of implementing genomic medicine in clinical practice for an early intervention and necessary support for the families.
Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8
/span> in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.
Sorrentino U, etal., J Neurol. 2024 May;271(5):2859-2865. doi: 10.1007/s00415-024-12271-x. Epub 2024 Mar 5.
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. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.
Shen C, etal., Mol Cell. 2015 Dec 17;60(6):847-59. doi: 10.1016/j.molcel.2015.10.033. Epub 2015 Nov 25.
The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were foun
d to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription.
Barnard RA, etal., Front Neurosci. 2015 Dec 17;9:477. doi: 10.3389/fnins.2015.00477. eCollection 2015.
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme
genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias toward genes involved in transcriptional regulation, such as chromatin modifiers. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8, a chromatin remodeling factor, may serve as a "master regulator" of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription and CHD8 binding site profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However, continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future.
Doummar D, etal., Ann Clin Transl Neurol. 2021 Oct;8(10):1986-1990. doi: 10.1002/acn3.51444. Epub 2021 Aug 20.
Originally described as a risk factor for autism, CHD8 loss-of-function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8-related phenotype with the
description of two unrelated patients who presented with childhood-onset progressive dystonia. Whole-exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild-to-moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder-associated genes whose mutations can also result in dystonia-dominant phenotypes.
Merner N, etal., Am J Med Genet A. 2016 May;170A(5):1225-35. doi: 10.1002/ajmg.a.37566. Epub 2016 Jan 20.
Mutations in chromodomain helicase DNA-binding domain 8 (CHD8) have been identified in independent genotyping studies of autism spectrum disorder. To better understand the phenotype associated with CHD8 mutations, we genotyp
ed all CHD8 exons in carefully assessed cohorts of autism (n = 142), schizophrenia (SCZ; n = 143), and intellectual disability (ID; n = 94). We identified one frameshift mutation, seven non-synonymous variants, and six synonymous variants. The frameshift mutation, p.Asn2092Lysfs*2, which creates a premature stop codon leading to the loss of 212 amino acids of the protein, was from an autism case on whom we present multiple clinical assessments and pharmacological treatments spanning more than 10 years. RNA and protein analysis support a model where the transcript generated from the mutant allele results in haploinsufficiency of CHD8. This case report supports the association of CHD8 mutations with classical autism, macrocephaly, infantile hypotonia, speech delay, lack of major ID, and psychopathology in late adolescence caused by insufficient dosage of CHD8. Review of 16 other CHD8 mutation cases suggests that clinical features and their severity vary considerably across individuals; however, these data support a CHD8 mutation syndrome, further highlighting the importance of genomic medicine to guide clinical assessment and treatment.
An Y, etal., Hum Genet. 2020 Apr;139(4):499-512. doi: 10.1007/s00439-020-02115-9. Epub 2020 Jan 24.
CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype-phenotype c
orrelations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p.Glu689X), a splice site variant (c.4818-1G>A) and a missense variant (c.3502T>A/p.Tyr1168Asn). Three of these were identified from a 445-member ASD cohort by ASD gene panel sequencing of the 96 subjects who remained negative after molecular testing for copy number variation, Rett syndrome, FragileX and tuberous sclerosis complex (TSC). The fourth (p.Glu689X) was detected separately by diagnostic trio exome sequencing. We used diagnostic instruments and a comprehensive review of phenotypes, including prenatal and postnatal growth parameters, developmental milestones, and dysmorphic features to compare these four subjects. In addition to autism, they also presented with prenatal onset macrocephaly, intellectual disability, overgrowth during puberty, sleep disorder, and dysmorphic features, including broad forehead with prominent supraorbital ridges, flat nasal bridge, telecanthus and large ears. For further comparison, we compiled a comprehensive list of CHD8 variants from the literature and databases, which revealed constitutive and somatic truncating variants in the HELIC (Helicase-C) domain in ASD and in cancer patients, respectively, but not in the general population. Furthermore, HELIC domain mutations were associated with a severe phenotype defined by a greater number of clinical features, lower verbal IQ, and a prominent, consistent pattern of overgrowth as measured by weight, height and head circumference. Overall, this study adds to the ASD-associated loss-of-function mutations in CHD8 and highlights the clinical importance of the HELIC domain of CHD8.
Zhao C, etal., Dev Cell. 2018 Jun 18;45(6):753-768.e8. doi: 10.1016/j.devcel.2018.05.022.
Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 dele
tion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.
Ostrowski PJ, etal., Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):557-564. doi: 10.1002/ajmg.c.31749. Epub 2019 Nov 13.
CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8
ight:700;'>CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference >=2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (<=15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.
Shingleton JR and Hemann MT, PLoS One. 2015 Nov 20;10(11):e0143275. doi: 10.1371/journal.pone.0143275. eCollection 2015.
Aberrant chromatin regulation is a frequent driver of leukemogenesis. Mutations in chromatin regulators often result in more stem-like cells that seed a bulk leukemic population. Inhibitors targeting these proteins represent an emerging class of therapeutics, and identifying further chromatin regula
tors that promote disease progression may result in additional drug targets. We identified the chromatin-modifying protein CHD8 as necessary for cell survival in a mouse model of BCR-Abl+ B-cell acute lymphoblastic leukemia. This disease has a poor prognosis despite treatment with kinase inhibitors targeting BCR-Abl. Although implicated as a risk factor in autism spectrum disorder and a tumor suppressor in prostate and lung cancer, the mechanism of CHD8's activity is still unclear and has never been studied in the context of hematopoietic malignancies. Here we demonstrate that depletion of CHD8 in B-ALL cells leads to cell death. While multiple B cell malignancies were dependent on CHD8 expression for survival, T cell malignancies displayed milder phenotypes upon CHD8 knockdown. In addition, ectopic expression of the Notch1 intracellular domain in a T cell malignancy partially alleviated the detrimental effect of CHD8 depletion. Our results demonstrate that CHD8 has a context-dependent role in cell survival, and its inhibition may be an effective treatment for B lymphoid malignancies.
While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical f
eatures of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs). Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation.
