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The histone deacetylase 4 (<jats:italic>HDAC4<\/jats:italic>) 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\u2013Gastaut syndrome. Brain magnetic resonance imaging revealed reduced white matter and polymicrogyria\u2010like cortical malformations, primarily in the fronto\u2010basal regions. Whole\u2010exome sequencing identified a novel de novo <jats:italic>HDAC4<\/jats:italic> 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 <jats:italic>HDAC4<\/jats:italic> in psychomotor development and cognitive function, expands the phenotypic spectrum associated with <jats:italic>HDAC4<\/jats:italic> mutations, and suggests a potential link to epilepsy and cortical malformations.<\/jats:p>","DOI":"10.1002\/ajmg.b.33029","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T07:56:10Z","timestamp":1743580570000},"page":"32-37","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phenotypic Manifestations of a New Variant in <i>HDAC4<\/i> Gene"],"prefix":"10.1002","volume":"198","author":[{"given":"Monica","family":"Ianniello","sequence":"first","affiliation":[{"name":"AMES, Centro Polidiagnostico Strumentale Srl  Casalnuovo di Napoli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Istituto Comprensivo Statale \u201cMassimo Troisi\u201d  San Giorgio a Cremano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2901-3855","authenticated-orcid":false,"given":"Alessandro","family":"Ottaiano","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Tumori di Napoli, IRCCS \u201cG. 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