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Here, we aimed to understand its role in NDD by characterizing novel or recurrent de novo variants at the molecular and cellular levels. We collected clinical data on individuals in whom\n                    <jats:italic>DPYSL5<\/jats:italic>\n                    missense variants were identified through clinical genetic assessment of NDD or following the identification of brain malformations in fetuses. Functional analyses of wild-type and variant DPYSL5 proteins were performed to evaluate their impact on in vitro neuronal development and maturation, using primary neuronal cultures from mouse embryonic brains or hiPSC-derived human neural stem cells. We describe six different missense variants in\n                    <jats:italic>DPYSL5<\/jats:italic>\n                    in nine individuals (including three fetuses), including the previously identified p.(Glu41Lys) recurrent mutation (in 2 individuals), a novel recurrent missense p.(Glu25Lys) de novo variant (in 3 individuals including 2 fetuses), and 3 novel candidates. Common features were developmental delay, intellectual disability, as well as brain malformations including agenesis of the corpus callosum for the N-terminal variants. Functional assays in differentiating mouse or human neuronal cultures revealed impairments in dendritic arborization, axonal elongation, and synaptic density. We thus expanded the functional characterization of\n                    <jats:italic>DPYSL5<\/jats:italic>\n                    variants in NDD with brain malformations, including at the fetal stage, highlighting a fundamental role of the\n                    <jats:italic>DPYSL5<\/jats:italic>\n                    gene in brain formation and functioning.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03364-8","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T06:39:30Z","timestamp":1763966370000},"page":"2178-2190","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Missense variants in DPYSL5 associated with neurodevelopmental disorders and brain malformations cause impaired neuronal maturation in 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The study complied with the principles set out in the Declaration of Helsinki. All mouse experiments were performed according to protocols approved by the French Ministry of research and by INSERM (Project authorization numbers 01456.03 and HC2021-03). The use of the hiPSC cell line ASE-9211 has been declared to the French ministry of Research (CODECOH reference number DC-2022-5113) and the generation of the edited\n                      WT\/p.Glu41Lys\n                      hiPSC line is included in a regulatory approval from the Ministry of Research (DUO 7675).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics declaration"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}