Phenotypic Manifestations of a New Variant in HDAC4 Gene

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Psychomotor development delays impact 1%-3% of children, presenting diverse motor, cognitive, and social impairments.
• The Histone Deacetylase 4 (HDAC4) gene is crucial for neurodevelopment and has been linked to developmental delays and autism spectrum disorders.

Purpose of the Study:

• To report a novel de novo mutation in the HDAC4 gene.
• To describe the expanded clinical and neuroimaging phenotype associated with this mutation.
• To investigate the role of HDAC4 in psychomotor development, epilepsy, and cortical malformations.

Main Methods:

• Whole-exome sequencing was used to identify genetic mutations.
• Clinical data and brain magnetic resonance imaging (MRI) were analyzed.
• Phenotypic features were correlated with the identified genetic mutation.

Main Results:

• A novel de novo HDAC4 mutation (p.Gln1046AspfsTer29; c.3136_3137delCA) was identified in a patient with global psychomotor delay.
• The patient presented with hypotonia, feeding difficulties, epilepsy (Lennox-Gastaut syndrome), reduced white matter, and polymicrogyria-like cortical malformations.
• Distinct craniofacial abnormalities and hypertrichosis were also observed.

Conclusions:

• This case underscores the critical role of HDAC4 in psychomotor development and cognitive function.
• The findings expand the known phenotypic spectrum of HDAC4 mutations.
• A potential association between HDAC4 mutations, epilepsy, and cortical malformations is suggested.