HDAC4

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

Basic information

Region (hg38): 2:239048167-239401654

Previous symbols: [ "BDMR" ]

Links

ENSG00000068024 ∙ NCBI:9759 ∙ OMIM:605314 ∙ HGNC:14063 ∙ Uniprot:P56524 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 2q37 microdeletion syndrome (Definitive), mode of inheritance: AD
• neurodevelopmental disorder with central hypotonia and dysmorphic facies (Moderate), mode of inheritance: AD
• 2q37 microdeletion syndrome (Limited), mode of inheritance: Unknown
• neurodevelopmental disorder with central hypotonia and dysmorphic facies (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Brachydacytly-mental retardation syndrome	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	20691407; 24715439
An individual with, among other manifestations, cardiovascular anomalies and sensorineural hearing loss, has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HDAC4 gene.

• not provided (368 variants)
• Inborn genetic diseases (43 variants)
• not specified (21 variants)
• Neurodevelopmental disorder with central hypotonia and dysmorphic facies (12 variants)
• Chromosome 2q37 deletion syndrome (9 variants)
• HDAC4-related condition (9 variants)
• Intellectual disability (5 variants)
• Chromosome 2q37 deletion syndrome;Neurodevelopmental disorder with central hypotonia and dysmorphic facies (4 variants)
• Intellectual disability, profound (1 variants)
• Brachydactyly syndrome type E (1 variants)
• Neurodevelopmental disorder with central hypotonia and dysmorphic facies;Chromosome 2q37 deletion syndrome (1 variants)
• See cases (1 variants)
• Syndromic intellectual disability (1 variants)
• Intellectual disability, severe (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HDAC4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	63	21	88
missense		3	106	24	6	139
nonsense			3			3
start loss						0
frameshift		1	8			9
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			6	11	5	22
non coding			2	60	92	154
Total	0	4	124	147	119

Variants in HDAC4

This is a list of pathogenic ClinVar variants found in the HDAC4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-239052918-C-T			Likely benign (May 08, 2020)
2-239052959-G-A			Likely benign (Jul 05, 2019)
2-239053021-G-A			Likely benign (Aug 08, 2019)
2-239053106-C-A			Likely benign (Oct 12, 2018)
2-239053127-C-T			Likely benign (May 14, 2018)
2-239053235-C-T			Likely benign (Feb 21, 2019)
2-239053442-G-A			Benign (Dec 09, 2023)
2-239053453-T-C			Likely benign (May 17, 2018)
2-239053467-C-T		Inborn genetic diseases	Uncertain significance (Nov 08, 2022)
2-239053470-C-T			Conflicting classifications of pathogenicity (Dec 02, 2022)
2-239053471-G-A			Likely benign (Dec 20, 2017)
2-239053479-C-T		Syndromic intellectual disability	Uncertain significance (Jul 02, 2021)
2-239053493-G-A		Inborn genetic diseases	Uncertain significance (Oct 04, 2022)
2-239053495-G-A			Likely benign (Dec 11, 2018)
2-239053504-G-A			Likely benign (Dec 02, 2022)
2-239053510-C-T			Likely benign (Jul 12, 2022)
2-239053516-G-A		HDAC4-related disorder	Conflicting classifications of pathogenicity (Aug 23, 2022)
2-239053523-TCGTTCTCGCAAGTCTGAGCCTCGATCAGAGAA-T			Uncertain significance (Mar 15, 2018)
2-239053537-CTG-C			Uncertain significance (Jul 18, 2019)
2-239053545-C-T		Inborn genetic diseases	Uncertain significance (Feb 05, 2024)
2-239053557-G-A			Likely benign (Mar 01, 2022)
2-239053565-G-GA			Uncertain significance (Jul 09, 2020)
2-239053596-A-G		Microcephaly	Uncertain significance (-)
2-239053794-T-C			Benign (Aug 18, 2019)
2-239053869-C-T			Benign (Dec 24, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HDAC4	protein_coding	protein_coding	ENST00000345617	26	353485

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	8.46e-10	123962	0	1	123963	0.00000403

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.93	497	718	0.693	0.0000521	7003
Missense in Polyphen		117	247.28	0.47315		2364
Synonymous	-2.67	391	329	1.19	0.0000279	2207
Loss of Function	7.02	0	57.4	0.00	0.00000270	622

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000901	0.00000901
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: 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);Human papillomavirus infection - Homo sapiens (human);Cell Cycle;MicroRNAs in cardiomyocyte hypertrophy;TarBasePathway;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Neural Crest Differentiation;Cardiac Hypertrophic Response;Initiation of transcription and translation elongation at the HIV-1 LTR;ATM Signaling Network in Development and Disease;VEGFA-VEGFR2 Signaling Pathway;Ethanol effects on histone modifications;Endochondral Ossification;RUNX2 regulates chondrocyte maturation;RUNX2 regulates bone development;Transcriptional regulation by RUNX2;Disease;Signal Transduction;Gene expression (Transcription);RUNX3 regulates p14-ARF;Transcriptional regulation by RUNX3;sumoylation by ranbp2 regulates transcriptional repression;Generic Transcription Pathway;SUMOylation of chromatin organization proteins;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;RNA Polymerase II Transcription;Signaling by NOTCH1;Signaling by NOTCH;TGF-beta super family signaling pathway canonical;SUMOylation;Signaling events mediated by HDAC Class II;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Diseases of signal transduction;Validated nuclear estrogen receptor alpha network;Sumoylation by RanBP2 regulates transcriptional repression;Signaling events mediated by HDAC Class III;NOTCH1 Intracellular Domain Regulates Transcription (Consensus)

Recessive Scores

• pRec: 0.310

Intolerance Scores

• loftool: 0.151
• rvis_EVS: -2.85
• rvis_percentile_EVS: 0.61

Haploinsufficiency Scores

• pHI: 0.467
• hipred: Y
• hipred_score: 0.783
• ghis: 0.556

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.895

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hdac4
• Phenotype: growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); muscle phenotype; craniofacial phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: hdac4
• Affected structure: palate
• Phenotype tag: abnormal
• Phenotype quality: cleft

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;skeletal system development;osteoblast development;chromatin remodeling;protein deacetylation;inflammatory response;nervous system development;positive regulation of cell population proliferation;negative regulation of cell population proliferation;positive regulation of lamellipodium assembly;negative regulation of myotube differentiation;regulation of cardiac muscle contraction by calcium ion signaling;response to denervation involved in regulation of muscle adaptation;cardiac muscle hypertrophy in response to stress;positive regulation of smooth muscle cell migration;histone deacetylation;protein sumoylation;B cell differentiation;positive regulation of protein sumoylation;peptidyl-lysine deacetylation;regulation of gene expression, epigenetic;B cell activation;response to drug;regulation of protein binding;negative regulation of DNA-binding transcription factor activity;positive regulation of neuron apoptotic process;negative regulation of osteoblast differentiation;negative regulation of glycolytic process;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of smooth muscle cell proliferation;regulation of skeletal muscle fiber development;positive regulation of DNA-binding transcription factor activity;response to interleukin-1;histone H3 deacetylation;histone H4 deacetylation;cellular response to mechanical stimulus;cellular response to tumor necrosis factor;cellular response to parathyroid hormone stimulus;negative regulation of pri-miRNA transcription by RNA polymerase II;positive regulation of reactive oxygen species biosynthetic process
• Cellular component: histone deacetylase complex;nucleus;nucleoplasm;cytoplasm;cytosol;transcriptional repressor complex;Z disc;neuromuscular junction;A band;actomyosin
• 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;transcription factor binding;zinc ion binding;SUMO transferase activity;protein kinase binding;potassium ion binding;NAD-dependent histone deacetylase activity (H3-K14 specific);protein deacetylase activity;activating transcription factor binding;identical protein binding;histone deacetylase binding;sequence-specific DNA binding;transcription regulatory region DNA binding;repressing transcription factor binding;promoter-specific chromatin binding