GeneBe

HDAC4

protein-coding

histone deacetylase 4, the group of Histone deacetylases, class IIA|MicroRNA protein coding host genes

Gene summary

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]

Previous symbols:
  • BDMR

MANE transcript

NM_001378414.1

Inheritance

AD

ClinVar variants

P:17U:323B:219

Top phenotype

Brachydacytly-mental retardation syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr2:239,048,168-239,401,654

External References & Databases

Ensembl (ENSG00000068024)NCBI Gene (9759)OMIM (605314)HGNC:14063GenCCUniProt (P56524)AlphaFoldClinVar (HDAC4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~353.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with central hypotonia and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859232

Submitter: PanelApp Australia

neurodevelopmental disorder with central hypotonia and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859232

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with central hypotonia and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859232

Submitter: G2P

2q37 microdeletion syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010886

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with central hypotonia and dysmorphic faciesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859232

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Brachydacytly-mental retardation syndromeAD

Manifestation: Craniofacial; 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

Comments: An individual with, among other manifestations, cardiovascular anomalies and sensorineural hearing loss, has been described

Refs: 20691407; 24715439Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HDAC4 variants in ClinVar

18 Conditions Cataloged
not providedTotal: 465
Inborn genetic diseasesTotal: 150
not specifiedTotal: 97
HDAC4-related disorderTotal: 68
Neurodevelopmental disorder with central hypotonia and dysmorphic faciesTotal: 51
Chromosome 2q37 deletion syndromeTotal: 15
Intellectual disabilityTotal: 9
Syndromic intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378414.1. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
133
clinvar
12
clinvar
 154
missense
4
clinvar
7
clinvar
286
clinvar
70
clinvar
4
clinvar
 371
nonsense
1
clinvar
6
clinvar
 7
start loss
0
frameshift
1
clinvar
3
clinvar
12
clinvar
 16
splice donor/acceptor (+/-2bp)
1
clinvar
10
clinvar
 11
Total71032320316559

Highest pathogenic variant AF is 0.000009298266

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 92 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001378414.1RefSeqNP_001365343.126MANE Select
ENST00000543185.6EnsemblENSP00000440481.326MANE Select
NM_001378415.1RefSeqNP_001365344.126Standard
NM_001378416.1RefSeqNP_001365345.126Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
hdac4Danio rerio

Structure: palate

Quality: cleft

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Apelin signaling pathway - Homo sapiens (human)
  • MicroRNAs in cancer - Homo sapiens (human)
  • Viral carcinogenesis - Homo sapiens (human)
  • Epstein-Barr virus infection - Homo sapiens (human)
  • Alcoholism - Homo sapiens (human)

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • skeletal system development
  • osteoblast development
  • chromatin remodeling
  • protein deacetylation

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • RNA polymerase II transcription factor binding
  • transcription corepressor activity
  • histone deacetylase activity
  • protein binding

Cellular Component

  • histone deacetylase complex
  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000345617
Coding exons
26
Length
353485
Individuals with no LoFs
123962
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
123963
p
0.00000403
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.934977180.6930.00005217003
Missense (PolyPhen)117247.280.473152364
Synonymous-2.673913291.190.00002792207
Loss of Function7.02057.40.000.00000270622

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000900.0000090rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1 (PubMed:27708256). {ECO:0000269|PubMed:10523670, ECO:0000269|PubMed:24413532, ECO:0000269|PubMed:27708256}.;
Disease
DISEASE: Brachydactyly-mental retardation syndrome (BDMR) [MIM:600430]: A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism. {ECO:0000269|PubMed:20691407, ECO:0000269|PubMed:23188045, ECO:0000269|PubMed:24715439}. Note=The gene represented in this entry is involved in disease pathogenesis. HDAC4 point mutations and chromosomal microdeletions encompassing this gene have been found in BDMR patients (PubMed:20691407, PubMed:24715439, PubMed:23188045). However, HDAC4 haploinsufficiency is not fully penetrant and multiple genes may contribute to manifestation of the full phenotypic spectrum (PubMed:24715439, PubMed:23188045). {ECO:0000269|PubMed:20691407, ECO:0000269|PubMed:23188045, ECO:0000269|PubMed:24715439}.;

Recessive Scores

pRec
0.310

Intolerance Scores

LoFtool
0.151
RVIS EVS
-2.85
RVIS percentile EVS
0.61

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.895

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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