CHD8

Chr 14

chromodomain helicase DNA binding protein 8

Also known as: AUTS18, HELSNF1, IDDAM

NCBI Gene: 57680 ENSG00000100888 UniProt: Q9HCK8

This gene encodes a chromodomain-helicase-DNA binding protein that regulates transcription, promotes cell proliferation, and controls RNA synthesis through epigenetic remodeling. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder with autism and macrocephaly. The protein's critical role in transcriptional regulation explains how haploinsufficiency leads to the neurodevelopmental phenotype.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.08

Clinical Summary— CHD8

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

218 unique Pathogenic / Likely Pathogenic· 713 VUS of 1712 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.08LOEUF

pLI 1.000

Z-score 10.12

OE 0.04 (0.02–0.08)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.95Z-score

OE missense 0.56 (0.53–0.59)

806 obs / 1441.3 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.08)

0≤0.351.4

Missense OE?0.56 (0.53–0.59)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 5 / 129.0Missense obs/exp: 806 / 1441.3Syn Z: 1.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCHD8-related autismLOFAD

This gene — mechanism propensity

0.3097th %ile

GOF

0.2895th %ile

LOF

0.79top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 83% of P/LP variants are LoF · LOEUF 0.08 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFOur 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.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31001818 ↗

ClinVar Variant Classifications

1712 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic132

Likely Pathogenic86

VUS713

Likely Benign542

Benign81

Conflicting122

132

Pathogenic

Likely Pathogenic

713

VUS

542

Likely Benign

Benign

122

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	123	7	2	0	132
Likely Pathogenic	58	26	2	0	86
VUS	8	646	45	14	713
Likely Benign	0	102	175	265	542
Benign	0	4	63	14	81
Conflicting	—				122
Total	189	785	287	293	1,676

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

35 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap CHD8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →