Human Gene Module / Chromosome 2 / HDAC4

HDAC4histone deacetylase 4

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 18
Rare Variants / Common Variants
12 / 3
Aliases
HDAC4, HD4,  HDACA,  HA6116,  HDAC-A, 
Associated Syndromes
Brachydactyly mental retardation syndrome
Chromosome Band
2q37.3
Associated Disorders
ID, ASD
Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations in the HDAC4 gene have been identified with brachydactyly mental retardation syndrome (Williams et al., 2010). Genetic association has been found between the HDAC4 gene and schizophrenia in a Korean population cohort (Kim et al., 2010).

Molecular Function

Regulation of transcription

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HDAC4 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation McKinsey TA , et al. (2000) No -
2 Support Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes Aldred MA , et al. (2004) No ASD or autistic features
3 Support Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals Casas KA , et al. (2004) No ASD or autistic features
4 Highly Cited Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis Vega RB , et al. (2004) No -
5 Highly Cited The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation Chen JF , et al. (2005) No -
6 Recent Recommendation Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4 Portal D , et al. (2006) No -
7 Recent Recommendation HDAC4 regulates neuronal survival in normal and diseased retinas Chen B and Cepko CL (2009) No -
8 Recent Recommendation A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation Hageman J , et al. (2010) No -
9 Recent Recommendation Association of histone deacetylase genes with schizophrenia in Korean population Kim T , et al. (2010) No -
10 Primary Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems Williams SR , et al. (2010) No ID
11 Recent Recommendation Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome Morris B , et al. (2012) No -
12 Positive Association Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Yes -
13 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
14 Positive Association Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
15 Recent Recommendation Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor Le TN , et al. (2019) No ASD or autistic features
16 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
17 Support - Zhou X et al. (2022) Yes -
18 Support - Takeyari S et al. (2023) No Learning disability
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 20691407 Williams SR , et al. (2010)
- - copy_number_loss De novo - - 20691407 Williams SR , et al. (2010)
insC - frameshift_variant De novo - - 20691407 Williams SR , et al. (2010)
c.611+1G>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.646C>T p.Pro216Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2363G>A p.Gly788Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.555G>A p.Ala185%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.108G>A p.Thr36%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1410_1411del p.Gln471ValfsTer65 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3074-3_3074-2insG - splice_site_variant Familial Maternal - 31452935 Feliciano P et al. (2019)
c.2204G>A p.Arg735Gln missense_variant Familial Paternal Multiplex 37020696 Takeyari S et al. (2023)
c.1510C>T p.Arg504Cys missense_variant Familial Paternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2565C>T;c.2580C>T;c.2637C>T;c.2499C>T p.(=) synonymous_variant - - - 20471694 Kim T , et al. (2010)
c.95-1199C>T;c.80-1199C>T;c.167-1199C>T;c.14-1199C>T A/G intron_variant - - - 23453885 Cross-Disorder Group of the Psychiatric Genomics Consortium (2013)
c.-2465T>A;c.-1440T>A;c.-1864T>A;c.-2150T>A - 2KB_upstream_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
SFARI Gene score
2S

Strong Candidate, Syndromic

Deletion or haploinsufficiency of the HDAC4 gene is thought to be responsible for brachydactyly-mental retardation syndrome (OMIM 600430; also known as 2q37 deletion syndrome), a form of syndromic autism in which a subset of individuals with this syndrome present with autism or autistic features (Williams et al., 2010). Aldred et al., 2004 observed autism or repetitive, hyperkinetic behaviors in 7/20 (35%) of individuals with 2q37 deletions, whereas Casas et al., 2004 observed similar features in 23% of individuals from a cohort of 66 with 2q37 deletions. Genotype and phenotype correlation in 103 individuals with 2q37 deletions or HDAC4 mutations in Le et al., 2019 found that autistic features or autism spectrum disorder was present in 30% of cases. A genome-wide association meta-analysis of 7387 ASD cases and 8567 controls in Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017 identified a polymorphism upstream of the HDAC4 gene with a P-value < 1.0E-04. Polymorphisms of this gene had previously demonstrated association with schizophrenia in a Korean case-control population (Kim et al., 2010) and significant association (P-value < 10-5) in a primary analysis of 33,332 cases (with ASD, ADHD, bipolar disorder, major depressive disorder, and schizophrenia) and 27,888 controls in the Psychiatric Genomics Consortium (Cross-Disorder Group of the Psychiatric Genomics Consortium 2013).

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

Deletion or haploinsufficiency of the HDAC4 gene is thought to be responsible for brachydactyly-mental retardation syndrome (OMIM 600430; also known as 2q37 deletion syndrome), a form of syndromic autism in which a subset of individuals with this syndrome present with autism or autistic features (Williams et al., 2010). Aldred et al., 2004 observed autism or repetitive, hyperkinetic behaviors in 7/20 (35%) of individuals with 2q37 deletions, whereas Casas et al., 2004 observed similar features in 23% of individuals from a cohort of 66 with 2q37 deletions. Genotype and phenotype correlation in 103 individuals with 2q37 deletions or HDAC4 mutations in Le et al., 2019 found that autistic features or autism spectrum disorder was present in 30% of cases. A genome-wide association meta-analysis of 7387 ASD cases and 8567 controls in Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017 identified a polymorphism upstream of the HDAC4 gene with a P-value < 1.0E-04. Polymorphisms of this gene had previously demonstrated association with schizophrenia in a Korean case-control population (Kim et al., 2010) and significant association (P-value < 10-5) in a primary analysis of 33,332 cases (with ASD, ADHD, bipolar disorder, major depressive disorder, and schizophrenia) and 27,888 controls in the Psychiatric Genomics Consortium (Cross-Disorder Group of the Psychiatric Genomics Consortium 2013).

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Deletion or haploinsufficiency of the HDAC4 gene is thought to be responsible for brachydactyly-mental retardation syndrome (OMIM 600430; also known as 2q37 deletion syndrome), a form of syndromic autism in which a subset of individuals with this syndrome present with autism or autistic features (Williams et al., 2010). Aldred et al., 2004 observed autism or repetitive, hyperkinetic behaviors in 7/20 (35%) of individuals with 2q37 deletions, whereas Casas et al., 2004 observed similar features in 23% of individuals from a cohort of 66 with 2q37 deletions. Genotype and phenotype correlation in 103 individuals with 2q37 deletions or HDAC4 mutations in Le et al., 2019 found that autistic features or autism spectrum disorder was present in 30% of cases. A genome-wide association meta-analysis of 7387 ASD cases and 8567 controls in Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017 identified a polymorphism upstream of the HDAC4 gene with a P-value < 1.0E-04. Polymorphisms of this gene had previously demonstrated association with schizophrenia in a Korean case-control population (Kim et al., 2010) and significant association (P-value < 10-5) in a primary analysis of 33,332 cases (with ASD, ADHD, bipolar disorder, major depressive disorder, and schizophrenia) and 27,888 controls in the Psychiatric Genomics Consortium (Cross-Disorder Group of the Psychiatric Genomics Consortium 2013).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
S
icon
4S

Increased from S to 4S

Description

Deletion or haploinsufficiency of the HDAC4 gene is thought to be responsible for brachydactyly-mental retardation syndrome (OMIM 600430; also known as 2q37 deletion syndrome), a form of syndromic autism in which a subset of individuals with this syndrome present with autism or autistic features (Williams et al., 2010). Aldred et al., 2004 observed autism or repetitive, hyperkinetic behaviors in 7/20 (35%) of individuals with 2q37 deletions, whereas Casas et al., 2004 observed similar features in 23% of individuals from a cohort of 66 with 2q37 deletions. Genotype and phenotype correlation in 103 individuals with 2q37 deletions or HDAC4 mutations in Le et al., 2019 found that autistic features or autism spectrum disorder was present in 30% of cases. A genome-wide association meta-analysis of 7387 ASD cases and 8567 controls in Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017 identified a polymorphism upstream of the HDAC4 gene with a P-value < 1.0E-04. Polymorphisms of this gene had previously demonstrated association with schizophrenia in a Korean case-control population (Kim et al., 2010) and significant association (P-value < 10-5) in a primary analysis of 33,332 cases (with ASD, ADHD, bipolar disorder, major depressive disorder, and schizophrenia) and 27,888 controls in the Psychiatric Genomics Consortium (Cross-Disorder Group of the Psychiatric Genomics Consortium 2013).

4/1/2019
S
icon
S

Increased from S to S

Description

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, haploinsufficiency in the HDAC4 gene has been identified with brachydactyly mental retardation syndrome (Williams et al., 2010). No other evidence exists that implicates this gene in autism.

Reports Added
[Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes.2004] [Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals.2004] [Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary g...2019]
4/1/2017
S
icon
S

Increased from S to S

Description

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, haploinsufficiency in the HDAC4 gene has been identified with brachydactyly mental retardation syndrome (Williams et al., 2010). No other evidence exists that implicates this gene in autism.

Reports Added
[Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.2013] [Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral probl...2010] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Association of histone deacetylase genes with schizophrenia in Korean population.2010] [Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation.2000] [Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.2004] [The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation.2005] [Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4.2006] [HDAC4 regulates neuronal survival in normal and diseased retinas.2009] [A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation.2010] [Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome.2012] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017]
1/1/2015
S
icon
S

Increased from S to S

Description

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, haploinsufficiency in the HDAC4 gene has been identified with brachydactyly mental retardation syndrome (Williams et al., 2010). No other evidence exists that implicates this gene in autism.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
Krishnan Probability Score

Score 0.57016026821676

Ranking 963/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99998972682083

Ranking 457/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93943178835099

Ranking 14208/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.46108056450122

Ranking 821/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AIB1 nuclear receptor coactivator 3 Human Protein Binding 8202 Q9Y6Q9
ANCO1 Ankyrin repeat domain-containing protein 11 Human Protein Binding 29123 Q6UB99
Csrp3 cysteine and glycine-rich protein 3 (cardiac LIM protein) Rat DNA Binding 117505 P50463
EFEMP2 EGF containing fibulin-like extracellular matrix protein 2 Human Protein Binding 30008 O95967
Fosl1 fos-like antigen 1 Rat DNA Binding 25445 P10158
HOXB13 homeobox B13 Human DNA Binding 10481 Q4KR72
HTR3C 5-hydroxytryptamine receptor 3C Human Protein Binding 170572 Q8WXA8
KRT38 keratin 38, type I Human Protein Binding 8687 O76015
LDOC1 Protein LDOC1 Human Protein Binding 23641 O95751
Lkb1 serine/threonine kinase 11 Mouse Protein Modification 20869 Q9WTK7
miR-133 microRNA 133a-1 Human RNA Binding 406922 N/A
Nppb natriuretic peptide B Rat DNA Binding 25105 P13205
TDP-43 TAR DNA-binding protein 43 Human RNA Binding 23435 Q13148
Tnfrsf12a tumor necrosis factor receptor superfamily, member 12a Rat DNA Binding 302965 Q80XX9
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