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Because a complete knockout of Chd8 causes embryonic lethality, we generated viable homozygous Chd8-mutant mice carrying the human CHD8-Asn2373LysfsX2 mutation using a hybrid (C57BL6\/J \u00d7 129\/Sv) genetic background. Compared to heterozygous\n                    <jats:italic>Chd8<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/N2373K<\/jats:italic>\n                    <\/jats:sup>\n                    mice, the homozygous\n                    <jats:italic>Chd8<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>N2373K\/N2373K<\/jats:italic>\n                    <\/jats:sup>\n                    mice showed more robust phenotypes, including increased ASD-related behaviors and brain volume, decreased cerebral blood volume\/flow, brain rhythms, and synaptic transmission, and ASD-related transcriptomic changes. Notably, while\n                    <jats:italic>Chd8<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/N2373K<\/jats:italic>\n                    <\/jats:sup>\n                    mice on a pure background predominantly displayed behavioral deficits in males, the homozygous mutants in the hybrid background exhibited more pronounced female phenotypes, suggesting the interaction of genetic background and mutation strength. A direct comparison of\n                    <jats:italic>Chd8<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/N2373K<\/jats:italic>\n                    <\/jats:sup>\n                    and\n                    <jats:italic>Chd8<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>N2373K\/N2373K<\/jats:italic>\n                    <\/jats:sup>\n                    mice on the same hybrid background across brain volume, cerebral blood flow, neuronal firing, synaptic transmission, and transcriptome revealed a gene dosage-dependent attenuation of sexual dimorphic phenotypes that varied by developmental stage and brain region. Transcriptomic analyses further implicated pathways related to synaptic function, RNA splicing, and mitochondrial activity in mediating differences in male\u2013female protection and susceptibility. Thus, a homozygous Chd8 mutation not only intensifies ASD-related traits but can also diminish typical sex-specific severity patterns, uncovering a novel link between mutation strength and sexual dimorphism in ASD.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03646-9","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T06:13:50Z","timestamp":1778307230000},"page":"5629-5645","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Homozygous CHD8 mutation intensifies ASD phenotypes and attenuates sex differences"],"prefix":"10.1038","volume":"31","author":[{"given":"Jinkyeong","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-528X","authenticated-orcid":false,"given":"Seungjoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8830-0512","authenticated-orcid":false,"given":"Eunkyu","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6194-9648","authenticated-orcid":false,"given":"Hwajin","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanhee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Han","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sooyeon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1105-5558","authenticated-orcid":false,"given":"Seongbin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heera","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jisoo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Gyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4227-9904","authenticated-orcid":false,"given":"Soogeun","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyojin","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Jin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8741-6177","authenticated-orcid":false,"given":"Heon Yung","family":"Gee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1960-4464","authenticated-orcid":false,"given":"Seong-Gi","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9726-4819","authenticated-orcid":false,"given":"Eunee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-6584","authenticated-orcid":false,"given":"Eunjoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"3646_CR1","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3389\/fnins.2015.00477","volume":"9","author":"RA Barnard","year":"2015","unstructured":"Barnard RA, Pomaville MB, O\u2019Roak BJ. 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