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Phenotypic Manifestations of a New Variant in HDAC4 Gene

Monica Ianniello,Valentina De Angelis,A. Ottaiano,Raffella Ruggiero,Roberto Sirica,Nadia Petrillo,Antonio Fico,Tania Cerbone,Cecilia Rosania,Raffaella Mormile,Carmine Picone,M. Santorsola,Giovanni Savarese

Published 2025 in American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

ABSTRACT

Psychomotor development delays affect 1%–3% of children and encompass a wide range of motor, cognitive, and social impairments. The histone deacetylase 4 (HDAC4) gene, critical for neurodevelopmental pathways, has been associated with developmental delays, autism spectrum disorders, and cognitive impairments. Here, we report a case of a female patient with global psychomotor developmental delay, hypotonia, and feeding difficulties since infancy. By the age of seven, she developed epilepsy, later diagnosed as Lennox–Gastaut syndrome. Brain magnetic resonance imaging revealed reduced white matter and polymicrogyria‐like cortical malformations, primarily in the fronto‐basal regions. Whole‐exome sequencing identified a novel de novo HDAC4 mutation (p.Gln1046AspfsTer29; c.3136_3137delCA), resulting in a frameshift and a premature stop codon. Additional phenotypic features included distinct craniofacial abnormalities and hypertrichosis. This report highlights the critical role of HDAC4 in psychomotor development and cognitive function, expands the phenotypic spectrum associated with HDAC4 mutations, and suggests a potential link to epilepsy and cortical malformations.

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