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In this study, we propose a novel mode of inheritance for <jats:italic>ATP9A<\/jats:italic>\u2010related disorders with the identification of five de novo heterozygous missense variants (p.(Thr393Arg), p.(Glu400Gln), p.(Lys461Glu), p.(Gly552Ala), and p.(His713Asp)), in patients with intellectual disability. In a patient with a similar phenotype, we also identified two truncating variants in <jats:italic>ATP9A<\/jats:italic> (p.(Arg145\u2009<jats:sup>\u2217<\/jats:sup>), p.(Glu901\u2009<jats:sup>\u2217<\/jats:sup>)), adding a novel family to the six already described in the literature with the recessive mode of inheritance. Functional studies were performed to assess the pathogenicity of these variants. Overexpression of four selected missense mutant forms of <jats:italic>Atp9a<\/jats:italic> in HeLa cells and in primary neuronal cultures led to a loss of mature dendritic spines. In HeLa cells, the endosomal localization of the protein encoded by three of these missense variants was preserved whereas the fourth remained blocked in the endoplasmic reticulum. To mimic the effect on neuronal morphology and spine density of nonsense variants, small hairpin RNAs (shRNAs) were used. They induced a decreased expression of <jats:italic>ATP9A<\/jats:italic>, affecting the neuronal arborization by decreasing the number of dendrites per neuron. Our results therefore demonstrate the pathogenicity of <jats:italic>ATP9A<\/jats:italic> heterozygous missense variants and confirm the role of <jats:italic>ATP9A<\/jats:italic> in neuronal maturation and in brain wiring during development. They strengthen the association of <jats:italic>ATP9A<\/jats:italic> with neurodevelopmental disorders and demonstrate that a double mode of inheritance should be considered for <jats:italic>ATP9A<\/jats:italic>\u2010related disorders.<\/jats:p>","DOI":"10.1155\/humu\/7085599","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T09:53:11Z","timestamp":1741773191000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Heterozygous Missense Variants in the ATPase Phospholipid Transporting 9A Gene, <i>ATP9A<\/i>, Alter Dendritic Spine Maturation and Cause Dominantly Inherited Nonsyndromic Intellectual 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