HDAC8

Chr XXLD

histone deacetylase 8

Also known as: CDA07, CDLS5, HD8, HDACL1, KDAC8, MRXS6, RPD3, WTS

NCBI Gene: 55869 ENSG00000147099 UniProt: Q9BY41 OMIM: 300269

This histone deacetylase catalyzes the deacetylation of lysine residues in histone N-terminal tails, repressing transcription in large multiprotein complexes. Loss-of-function mutations cause Cornelia de Lange syndrome 5, inherited in an X-linked dominant pattern. The high constraint scores (pLI 0.98, LOEUF 0.30) indicate the gene is highly intolerant to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLDLOEUF 0.301 OMIM phenotype

Clinical Summary— HDAC8

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Gene-Disease Validity (ClinGen)

Cornelia de Lange syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

87 unique Pathogenic / Likely Pathogenic· 109 VUS of 435 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.977

Z-score 3.47

OE 0.06 (0.02–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.82Z-score

OE missense 0.35 (0.28–0.44)

51 obs / 147.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.30)

0≤0.351.4

Missense OE?0.35 (0.28–0.44)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 1 / 16.0Missense obs/exp: 51 / 147.4Syn Z: 0.34

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHDAC8-related Cornelia de Lange syndromeLOFXLR

definitiveHDAC8-related Cornelia de Lange syndromeLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.3495th %ile

GOF

0.3491th %ile

LOF

0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 49% of P/LP variants are LoF · LOEUF 0.30 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

ClinVar Variant Classifications

435 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39

Likely Pathogenic48

VUS109

Likely Benign128

Benign36

Conflicting11

Pathogenic

Likely Pathogenic

109

VUS

128

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	6	6	0	39
Likely Pathogenic	16	28	4	0	48
VUS	3	86	15	5	109
Likely Benign	1	12	58	57	128
Benign	1	5	20	10	36
Conflicting	—				11
Total	48	137	103	72	371

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

51 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap HDAC8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →