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HDAC4 Gene Curation

HDAC4 Gene Curation

Owned by Andrea Oza
Last updated: 2025-04-04

Gene-disease assertions not curated here (add link or write note):

Disease

Neurodevelopmental disorder with central hypotonia and dysmorphic facies

Disease

Neurodevelopmental disorder with central hypotonia and dysmorphic facies

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - strong by Invitae, limited by Ambry (but Ambry actually classifies Pro248L as pathogenic in ClinVar for this disorder, so it seems their curation in GenCC is not accurate). No BabySeq curation.

Clinical Validity Scoring Notes and points

This gene is a histone deacyetylase, which are regulators of chromatin structure and gene expression.

PMID: 33537682

  • Per table 1, there are 7 patients with a similar phenotype and de novo variants in HDAC4. Phenotype includes speech delay, delayed walking, seizures, central hypotonia, abnormal brain MRI (cerebral atrophy, cerebellar atrophy, and other abnormalities, facial features, poor suck / feeding difficulties, sleep disturbance, kyphosis/scoliosis, hip anomalies, visual problems.

  • Propose GOF mechanism, variants located within 14-3-3 binding site

  • c.731C>A p.T244K - absent gnomAD v4. De novo in patient 1. 1 POINT

    • Fig 4 - variant has significantly reduced affinity for 14-3-3B compared to wt +0.5 point

  • c.740A>G p.E247G - absent gnomAD v4. De novo in patient 2 1 POINT

    • Fig 4 - variant has significantly reduced affinity for 14-3-3B compared to wt +0.5 point

  • c.742C>G p.P248A - absent gnomAD v4 De novo in patient 3 1 POINT

  • c.743C>T p.P248L - absent gnomAD v4 De novo in patients 4-7. 4 POINTS (1 for each patient)

PMID: 40167013

  • c.3136_3137delCA p.Gln1046AspfsTer29, absent gnomAD v4, NOT predicted to undergo NMD (PTC at p.1080), de novo in a patient with hypotonia, developmental delays, epilepsy with poor seizure control, abnormal brain MRI - reduced white matter, polymicrogyria-like cortical malformation, enlarged ventricles. 0.5 POINTS

Clinical Validity Points Total

8.5

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

At least Moderate

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown

PMID: 33537682 - proposes GOF, but there isn’t much functional evidence to support this.

Three reported variants are located within a conserved 14-3-3 binding domain:

image-20250404-180653.png

 

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

congenital

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

severe

Clinical Features

  • Phenotype includes speech delay, delayed walking, seizures, central hypotonia, abnormal brain MRI (cerebral atrophy, cerebellar atrophy, and other abnormalities, facial features, poor suck / feeding difficulties, sleep disturbance, kyphosis/scoliosis, hip anomalies, visual problems.

Sources: 33537682, 40167013

HPO Terms

https://hpo.jax.org/app/

 

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

The HDAC4 is associated with HDAC4-related neurodevelopmental disorder with central hypotonia and dysmorphic facies. The clinical features include speech delay, delayed walking, seizures, central hypotonia, abnormal brain MRI (cerebral atrophy, cerebellar atrophy, and other abnormalities, facial features, poor suck / feeding difficulties, sleep disturbance, kyphosis/scoliosis, hip anomalies, visual problems. All variants reported to date are de novo. This gene is a histone deacyetylase, which are regulators of chromatin structure and gene expression (PMID: 33537682, 40167013).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, SDSM-PNV, 04/04/2025