CHD4

Chr 12AD

chromodomain helicase DNA binding protein 4

Also known as: CHD-4, Mi-2b, Mi2-BETA, SIHIWES

NCBI Gene: 1108 ENSG00000111642 UniProt: Q14839 OMIM: 603277

CHD4 encodes an ATP-dependent chromatin-remodeling factor that binds and distorts nucleosomal DNA as a component of the histone deacetylase NuRD complex, participating in chromatin remodeling, transcriptional repression, and DNA repair. Loss-of-function mutations cause Sifrim-Hitz-Weiss syndrome, inherited in an autosomal dominant pattern. The protein is involved in neurogenesis and localizes to damaged chromatin to promote double-strand break repair.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Patients with dermatomyositis develop antibodies against this protein. Somatic mutations in this gene are associated with serous endometrial tumors. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— CHD4

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · 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

73 unique Pathogenic / Likely Pathogenic· 397 VUS of 831 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHD4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 8.76

OE 0.09 (0.06–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

6.34Z-score

OE missense 0.46 (0.43–0.50)

504 obs / 1094.3 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.09 (0.06–0.16)

0≤0.351.4

Missense OE?0.46 (0.43–0.50)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 10 / 108.4Missense obs/exp: 504 / 1094.3Syn Z: -0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCHD4-related syndromic intellectual disability with or without congenital heart diseaseLOFAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.2995th %ile

LOF

0.76top 10%

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

LOFprediction above median · 21% of P/LP variants are LoF · LOEUF 0.16

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

ClinVar Variant Classifications

831 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic59

VUS397

Likely Benign215

Benign50

Conflicting28

Pathogenic

Likely Pathogenic

397

VUS

215

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	12	1	0	14
Likely Pathogenic	14	45	0	0	59
VUS	23	349	19	6	397
Likely Benign	1	24	88	102	215
Benign	0	6	16	28	50
Conflicting	—				28
Total	39	436	124	136	763

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

View in ClinVar →

45 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap CHD4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →