CHD8

protein-coding

chromodomain helicase DNA binding protein 8, the group of Small nucleolar RNA protein coding host genes

Gene summary

This gene encodes a member of the chromodomain-helicase-DNA binding protein family, which is characterized by a SNF2-like domain and two chromatin organization modifier domains. The encoded protein also contains brahma and kismet domains, which are common to the subfamily of chromodomain-helicase-DNA binding proteins to which this protein belongs. This gene has been shown to function in several processes that include transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. Allelic variants of this gene are associated with autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2016]

Previous symbols:

HELSNF1

MANE transcript

NM_001170629.2

Inheritance

ClinVar variants

P:272U:888B:521

Top phenotype

Intellectual developmental disorder with autism and macrocephaly

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr14:21,385,194-21,456,126

External References & Databases

Ensembl (ENSG00000100888)

Transcript & Mutation Effects

hg38 • Region Span ~70.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005260

Submitter: G2P

congenital myasthenic syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018940

Submitter: Ambry Genetics

intellectual disabilitySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CHD8* was first reported in relation to autosomal dominant autism spectrum disorder in 2012 (O'Roak et al., PMID: 22495309). *CHD8* encodes a member of the chromodomain helicase DNA-binding (CHD) protein family involved in chromatin remodeling. In addition to an increased likelihood of a diagnosis of autism spectrum disorder, individuals with pathogenic variants in *CHD8* have variable degrees of intellectual disability, an overgrowth phenotype with macrocephaly and increased height, dysmorphic facial features, and gastrointestinal problems (PMID: 24998929). We therefore decided to curate for the generic term complex neurodevelopmental disorder. Eight truncating variants (frameshift, nonsense) that have been reported in 8 probands in 4 publications (PMIDs: 22495309, 24998929, 26789910, 27824329) are included in this curation. Most variants are *de novo*; one individual inherited a *CHD8* variant from a heterozygous mother who had some autistic features but had not been clinically diagnosed. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by zebrafish and mouse models. In summary, there is definitive evidence supporting the relationship between *CHD8* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 16, 2018 (SOP Version 5). As of February 2026, this record underwent administrative updates to include edits to the evidence summary and update scoring to be consistent with SOP Version 12. No new evidence was added, and the classification remains the same.

intellectual developmental disorder with autism and macrocephalySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014017

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder with autism and macrocephalyAD

Manifestation: Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21572417; 22495306; 22495309; 22495311; 22521361; 23160955; 24998929; 31001818

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHD8 variants in ClinVar

27 Conditions Cataloged

not providedTotal: 1496

Inborn genetic diseasesTotal: 398

Intellectual developmental disorder with autism and macrocephalyTotal: 266

CHD8-related disorderTotal: 118

not specifiedTotal: 116

Paediatric disordersTotal: 31

Intellectual disabilityTotal: 16

Autism spectrum disorderTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001170629.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			18 clinvar	300 clinvar	13 clinvar	331
missense	7 clinvar	39 clinvar	850 clinvar	205 clinvar	3 clinvar	1104
nonsense	59 clinvar	28 clinvar	8 clinvar			95
start loss			1 clinvar			1
frameshift	68 clinvar	42 clinvar	2 clinvar			112
splice donor/acceptor (+/-2bp)	11 clinvar	18 clinvar	9 clinvar			38
Total	145	127	888	505	16	1681

Highest pathogenic variant AF is 0.000013638928

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001170629.2	RefSeq	NP_001164100.1	37	MANE Select
ENST00000646647.2	Ensembl	ENSP00000495240.1	37	MANE Select
NM_020920.4	RefSeq	NP_065971.2	37	Standard
ENST00000430710.8	Ensembl	ENSP00000406288.3	37	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
chd8	Danio rerio	Structure: enteric neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

chd8

Danio rerio

Structure: enteric neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Wnt signaling pathway - Homo sapiens (human)
Wnt Signaling Pathway
Signaling by WNT
Signal Transduction
Deactivation of the beta-catenin transactivating complex

Biological Process

negative regulation of transcription by RNA polymerase II
in utero embryonic development
brain development
Wnt signaling pathway
DNA duplex unwinding

Molecular Function

p53 binding
DNA binding
DNA helicase activity
chromatin binding
protein binding

Cellular Component

nucleus
nucleoplasm
protein-containing complex
MLL1 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399982
Coding exons: 37
Length: 70933
Individuals with no LoFs: 124641
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 124653
p: 0.0000481

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.95	806	1.44e+3	0.559	0.0000827	16853
Missense (PolyPhen)		166	516.11	0.32164		5933
Synonymous	1.03	473	502	0.941	0.0000254	5048
Loss of Function	10.1	5	129	0.0388	0.00000800	1415

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000066	0.000065	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000027	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA helicase that acts as a chromatin remodeling factor and regulates transcription. Acts as a transcription repressor by remodeling chromatin structure and recruiting histone H1 to target genes. Suppresses p53/TP53-mediated apoptosis by recruiting histone H1 and preventing p53/TP53 transactivation activity. Acts as a negative regulator of Wnt signaling pathway by regulating beta-catenin (CTNNB1) activity. Negatively regulates CTNNB1- targeted gene expression by being recruited specifically to the promoter regions of several CTNNB1 responsive genes. Involved in both enhancer blocking and epigenetic remodeling at chromatin boundary via its interaction with CTCF. Acts as a suppressor of STAT3 activity by suppressing the LIF-induced STAT3 transcriptional activity. Also acts as a transcription activator via its interaction with ZNF143 by participating in efficient U6 RNA polymerase III transcription. {ECO:0000255|HAMAP- Rule:MF_03071, ECO:0000269|PubMed:17938208, ECO:0000269|PubMed:18378692}.;
Disease: DISEASE: Autism 18 (AUTS18) [MIM:615032]: A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate mental retardation. {ECO:0000269|PubMed:23160955, ECO:0000269|PubMed:26637798}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.121
RVIS EVS: -2.34
RVIS percentile EVS: 1.18

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.948

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium