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Our findings define a monogenic disorder marked by neuropsychiatric features (including autism and ADHD), mild to moderate neurodevelopmental delay, and variable brain growth \u2013 most commonly macrocephaly and in one case reduced head circumference. To investigate the effect\n                    <jats:italic>of WDFY3<\/jats:italic>\n                    LoF we performed knockdown (KD) in the human neuroblastoma cell line SH-SY5Y and used a\n                    <jats:italic>Wdfy3<\/jats:italic>\n                    -haploinsufficient mouse model.\n                    <jats:italic>WDFY3<\/jats:italic>\n                    KD impaired clearance of protein aggregates and decreased protein levels of the ubiquitin-binding protein p62. Transcriptomic analyses identified dysregulation in gene networks that are primarily involved in nervous system development, neuron projection, MAPK\/ERK1\/2, and WNT\/\u03b2-catenin signaling. This was confirmed at protein level. Neuronal cell proliferation was increased, as evidenced by elevated cell counts and proliferation markers Ki-67 and\n                    <jats:italic>PCNA<\/jats:italic>\n                    . Conversely, neuronal cell differentiation was impaired, as indicated by reduced neurite outgrowth. We show that \u03b2-catenin is downregulated, while\n                    <jats:italic>GSK3B<\/jats:italic>\n                    is upregulated. LiCl activates WNT\/\u03b2-catenin signaling by inhibiting GSK3B. We thus tested LiCl treatment, which significantly increased\n                    <jats:italic>WDFY3<\/jats:italic>\n                    expression. Moreover, in vitro treatment improved the neurite branching capacity of\n                    <jats:italic>Wdfy3<\/jats:italic>\n                    -haploinsufficient neurons above the level of the wild type, although this specific effect appeared independent of WNT\/\u03b2-catenin signaling. In sum, we expand on the phenotype related to\n                    <jats:italic>WDFY3<\/jats:italic>\n                    LoF and provide insights into the pathophysiology using in vitro human and murine neuronal models. Our findings suggest that LiCl may serve as a potential therapeutic strategy for patients with\n                    <jats:italic>WDFY3<\/jats:italic>\n                    LoF variants.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03844-5","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:45:02Z","timestamp":1790469902000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lithium chloride in vitro treatment shows potential to rescue the neuronal phenotype caused by WDFY3 haploinsufficiency"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9732-8074","authenticated-orcid":false,"given":"Moritz 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Authors affiliated with GeneDx [\n                      \n                      ] are employees of GeneDx, LLC. Ah MR is currently employed by Natera, Inc.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All methods were performed in accordance with the relevant local guidelines and regulations. This study was approved and monitored by the ethics committee of the University of Leipzig, Germany (224\/16-ek and 402\/16-ek). Animal handling protocols were approved by the University of California at Davis Institutional Animal Care and Use Committee overseen by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International accreditation program and in compliance with the ARRIVE [\n                      \n                      ] and NIH guidelines [\n                      \n                      ]. Institutional ethics approval was not required if testing was part of routine clinical care. Written informed consent to participate was obtained from all participants or their legal guardians. Written informed consent for publication of any identifiable images was obtained from all individual participants or their legal guardians.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}