HDAC8

protein-coding

histone deacetylase 8, the group of Histone deacetylases, class I

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 I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Previous symbols:

HDACL1
WTS
MRXS6

MANE transcript

NM_018486.3

Inheritance

AD, XL

ClinVar variants

P:103U:152B:89

Top phenotype

Cornelia de Lange syndrome 5

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chrX:72,329,516-72,573,101

External References & Databases

Ensembl (ENSG00000147099)

Transcript & Mutation Effects

hg38 • Region Span ~243.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Cornelia de Lange syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016033

Submitter: Orphanet

Wilson-Turner syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010665

Submitter: Orphanet

Cornelia de Lange syndrome 5DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010471

Submitter: G2P

Cornelia de Lange syndrome 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010471

Submitter: Labcorp Genetics (formerly Invitae)

Cornelia de Lange syndrome 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010471

Submitter: Ambry Genetics

Cornelia de Lange syndrome 5STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010471

Submitter: PanelApp Australia

Cornelia de Lange syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0016033

Submitter: ClinGen

*HDAC8* was first reported in relation to X-linked Cornelia de Lange syndrome (CdLS) in 2012 (Deardorff et al., PMID: 22885700). *HDAC8* variants expand the phenotypic spectrum of classic CdLS to include delayed closure of the anterior fontanelle, hypertelorism, hooding of eyelids, a wide nose and dental anomalies (PMIDs: 24403048, 26671848). Both males and females can be affected, although in females, the severity is influenced by the pattern of X-chromosome inactivation. Nine variants (missense, nonsense, frameshift, splice) that have been reported in 9 probands in 4 publications (PMIDs: 22885700, 22889856, 25102094, 29519750) are included in this curation. Variants in this gene usually occur *de novo* but segregation with disease was observed in 11 members of a Dutch family (Harakalova et al., 2012, PMID: 22889856). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by *in vitro* functional assays, rescue in patient cells, and animal models. In summary, there is definitive evidence supporting the relationship between *HDAC8* and X-linked Cornelia de Lange syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 11, 2018 (SOP Version 5).

Clinical Genomic Database (CGD)

Cornelia de Lange syndrome 5XL

Manifestation: Craniofacial; Dental; 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

Refs: 1746601; 22885700; 24403048; 25209348; 25644381

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HDAC8 variants in ClinVar

21 Conditions Cataloged

Cornelia de Lange syndrome 5Total: 290

not providedTotal: 100

Inborn genetic diseasesTotal: 43

not specifiedTotal: 26

HDAC8-related disorderTotal: 10

Intellectual disabilityTotal: 7

HDAC8-related disordersTotal: 6

Cornelia de Lange syndrome 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018486.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			12 clinvar	57 clinvar	10 clinvar	79
missense	10 clinvar	37 clinvar	118 clinvar	17 clinvar	5 clinvar	187
nonsense	11 clinvar	6 clinvar	8 clinvar			25
start loss						0
frameshift	12 clinvar	6 clinvar				18
splice donor/acceptor (+/-2bp)	9 clinvar	12 clinvar	14 clinvar			35
Total	42	61	152	74	15	344

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 121 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018486.3	RefSeq	NP_060956.1	11	MANE Select
ENST00000373573.9	Ensembl	ENSP00000362674.3	11	MANE Select
NM_001166418.2	RefSeq	NP_001159890.1	9	Standard
NM_001166419.2	RefSeq	NP_001159891.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Viral carcinogenesis - Homo sapiens (human)
Alcoholism - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
Cell Cycle
Neural Crest Differentiation

Biological Process

negative regulation of transcription by RNA polymerase II
chromatin organization
chromatin assembly or disassembly
sister chromatid cohesion
negative regulation of protein ubiquitination

Molecular Function

histone deacetylase activity
protein binding
transcription factor binding
Hsp70 protein binding
NAD-dependent histone deacetylase activity (H3-K14 specific)

Cellular Component

histone deacetylase complex
nuclear chromosome
nucleus
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373573
Coding exons: 11
Length: 243588
Individuals with no LoFs: 121907
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 121908
p: 0.00000410

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.82	51	147	0.346	0.0000111	2472
Missense (PolyPhen)		4	61.321	0.06523		1001
Synonymous	0.339	54	57.3	0.943	0.00000451	718
Loss of Function	3.47	1	16.0	0.0625	0.00000129	255

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00014	0.00010	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

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. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. {ECO:0000269|PubMed:10748112, ECO:0000269|PubMed:10922473, ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:22885700}.;
Disease: DISEASE: Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:22885700}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Wilson-Turner X-linked mental retardation syndrome (WTS) [MIM:309585]: A neurologic disorder characterized by severe intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Affected females have a milder phenotype than affected males. {ECO:0000269|PubMed:22889856}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.487
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

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