HDAC4

Chr 2AD

histone deacetylase 4

Also known as: AHO3, BDMR, HA6116, HD4, HDAC-4, HDAC-A, HDACA, NEDCHF

NCBI Gene: 9759 ENSG00000068024 UniProt: P56524 OMIM: 605314

HDAC4 encodes a class II histone deacetylase that removes acetyl groups from core histones to regulate gene transcription and plays a crucial role in muscle development through interactions with MEF2 transcription factors. Mutations cause neurodevelopmental disorder with central hypotonia and dysmorphic facies with autosomal dominant inheritance. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.052), indicating that even heterozygous disruption can cause significant developmental effects.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.051 OMIM phenotype

Clinical Summary— HDAC4

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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

1 unique Pathogenic / Likely Pathogenic· 104 VUS of 194 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 →

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GeneReview available — HDAC4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.05LOEUF

pLI 1.000

Z-score 7.02

OE 0.00 (0.00–0.05)

Highly constrained

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

Missense Constraint?

2.93Z-score

OE missense 0.69 (0.64–0.75)

497 obs / 717.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.05)

0≤0.351.4

Missense OE?0.69 (0.64–0.75)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 0 / 57.4Missense obs/exp: 497 / 717.6Syn Z: -2.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHDAC4-related intellectual developmental disorderOTHERAD

This gene — mechanism propensity

0.3694th %ile

GOF

0.4184th %ile

LOF

0.77top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.05

GOF1 literature citation

Literature Evidence

GOFFurthermore, we show that a truncated form of HDAC4 encoded by an allele associated with mental retardation is a gain-of-function nuclear repressor that abolishes transcription and synaptic transmission despite the loss of the deacetylase domain.1

LOFHaploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.2

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

References

ClinVar Variant Classifications

194 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS104

Likely Benign43

Benign2

Conflicting3

Pathogenic

104

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	1	96	6	1	104
Likely Benign	0	13	11	19	43
Benign	0	1	1	0	2
Conflicting	—				3
Total	1	111	18	20	153

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

View in ClinVar →

2 pathogenic / likely-pathogenic (of 6) ClinVar copy-number / structural variants overlap HDAC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →