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

LOFmechanismADLOEUF 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

30 unique Pathogenic / Likely Pathogenic· 266 VUS of 500 total submissions

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Clinical Trials

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

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GeneReview available — HDAC4

Authoritative clinical overview · Recommended first read

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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 OE0.00 (0.00–0.05)

0≤0.351.4

Missense OE0.69 (0.64–0.75)

0≤0.61.4

Synonymous OE1.19

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHDAC4-related brachydactyly-intellectual developmental disorder syndromeLOFAD

strongHDAC4-related intellectual disabilityOTHERAD

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.PMID:23141539

LOFHaploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.PMID:20691407

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