Phenotypic manifestations of a new variant in HDAC4 gene.

Background: Psychomotor development delays, impacting up to 1–3% of children, represent a broad spectrum of motor, cognitive, and social impairments. While these delays are often multifactorial, genetic mutations are increasingly recognized as significant contributors, especially in severe cases. Histone deacetylase 4 (HDAC4), a gene integral to neurodevelopmental pathways, has been implicated in developmental delays, autism spectrum disorders, and cognitive impairments. This study describes a novel HDAC4 mutation associated with psychomotor developmental delay, contributing valuable insights into the role of HDAC4 in neurodevelopment. Methods: We performed genetic testing on a female patient presenting with global psychomotor developmental delay, hypotonia, and feeding difficulties since infancy. At age seven, she developed epilepsy, diagnosed as Lennox-Gastaut syndrome. Genetic analysis, including sequencing and karyotyping, was conducted, along with detailed phenotypic characterization, neuroimaging, and follow-up evaluations. Results: A novel de novo HDAC4 mutation (p.Gln1046AspfsTer29; c.3136_3137delCA) was identified, leading to a frameshift and premature stop codon. Phenotypic manifestations included developmental delays, epilepsy, distinct craniofacial features, hypertrichosis, and hypotonia. MRI revealed reduced white matter and polymicrogyria-like cortical malformations, predominantly in fronto-basal regions. Conclusions: This newly identified HDAC4 mutation underscores the gene's crucial role in psychomotor development and cognitive function. Our findings expand the phenotypic spectrum of HDAC4 mutations, suggesting a link with epilepsy and cortical malformations. Further studies are warranted to elucidate HDAC4's neurodevelopmental mechanisms and explore therapeutic interventions targeting histone deacetylation pathways.