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CDH presents as a spectrum of forms and severities, with diaphragm defects arising in the dorsal\/posterior region typically correlating with more severe pulmonary disease and higher risk of mortality than those appearing in ventral\/anterior regions. The genetic etiology underlying CDH is complex, with many genes implicated showing variable expressivity and incomplete penetrance in both human patients and mouse models. Here we present\n                  <jats:italic>in vivo<\/jats:italic>\n                  validation of two genes previously unassociated with CDH: the CDC42-interacting kinase\n                  <jats:italic>CDC42BPB<\/jats:italic>\n                  ; and\n                  <jats:italic>CNOT1<\/jats:italic>\n                  , a scaffolding protein of the CCR4-NOT protein complex, critical for mRNA regulation through modifications such as deadenylation. Each gene was found to have a damaging,\n                  <jats:italic>de novo<\/jats:italic>\n                  missense variant in a recent large-scale CDH patient sequencing screen. Loss of\n                  <jats:italic>Cdc42bpb<\/jats:italic>\n                  leads to ventral diaphragmatic hernias, heart septal defects and minor lung epithelial differentiation defects in mouse embryos. Installation of the orthologous patient-specific missense variant through CRISPR\/Cas9 editing leads to less severe ventral diaphragm defects. Mouse embryos with either one or two copies of the orthologous\n                  <jats:italic>Cnot1<\/jats:italic>\n                  variant, c.1867C&gt;T (p.R623W), develop dorsal diaphragmatic hernias with low (&lt;50%) penetrance, and mutants showed alterations in mRNA isoform expression consistent with the molecular role of\n                  <jats:italic>Cnot1<\/jats:italic>\n                  in RNA splicing. These results underscore the power of\n                  <jats:italic>in vivo<\/jats:italic>\n                  functional modeling to validate genes and patient-specific variants uncovered by patient sequencing, reveal two previously unrecognized genetic causes of CDH, and highlight the heterogeneity of different patient anatomic presentations.\n                <\/jats:p>","DOI":"10.64898\/2026.02.24.707527","type":"posted-content","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T19:10:12Z","timestamp":1772133012000},"source":"Crossref","is-referenced-by-count":0,"title":["Modeling patient variants of\n                  <i>Cnot1<\/i>\n                  and\n                  <i>Cdc42bpb<\/i>\n                  results in distinct forms of congenital diaphragmatic hernia in mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3642-1707","authenticated-orcid":false,"given":"Eric L.","family":"Bogenschutz","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Carpenter","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameleen","family":"Wong","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Palmer","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7170-9568","authenticated-orcid":false,"given":"Aalekh","family":"Mehta","sequence":"additional","affiliation":[{"name":"Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5991-6415","authenticated-orcid":false,"given":"Yannick","family":"Ledermann","sequence":"additional","affiliation":[{"name":"Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Heffner","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5565-0619","authenticated-orcid":false,"given":"Kathy J.","family":"Snow","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9433-210X","authenticated-orcid":false,"given":"Carol","family":"Bult","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1299-5979","authenticated-orcid":false,"given":"Yufeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5502-4497","authenticated-orcid":false,"given":"Patricia K.","family":"Donahoe","sequence":"additional","affiliation":[{"name":"Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA, 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