{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T04:28:21Z","timestamp":1793766501126,"version":"4.6.1"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T00:00:00Z","timestamp":1665014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS072129"],"award-info":[{"award-number":["R01 NS072129"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-162225"],"award-info":[{"award-number":["PJT-162225"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-77556"],"award-info":[{"award-number":["MOP-77556"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-153053"],"award-info":[{"award-number":["PJT-153053"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-159839"],"award-info":[{"award-number":["PJT-159839"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Howard Hughes Medical Institute Investigator"},{"DOI":"10.13039\/100006086","name":"Office of Strategic Coordination","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"Office of the NIH Director","doi-asserted-by":"publisher","award":["U01HG007709"],"award-info":[{"award-number":["U01HG007709"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007856","name":"Baylor College of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007857","name":"IDDRC","doi-asserted-by":"publisher","award":["P50HD103555"],"award-info":[{"award-number":["P50HD103555"]}],"id":[{"id":"10.13039\/100007857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR\/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1\/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).<\/jats:p>","DOI":"10.1093\/brain\/awac364","type":"journal-article","created":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T08:11:10Z","timestamp":1664871070000},"page":"1373-1387","source":"Crossref","is-referenced-by-count":45,"title":["Loss-of-function variants in\n                    <i>MYCBP2<\/i>\n                    cause neurobehavioural phenotypes and corpus callosum defects"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8177-4048","authenticated-orcid":false,"given":"Lama","family":"AlAbdi","sequence":"first","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University , Riyadh 11362 , Saudi Arabia"},{"name":"Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center , Riyadh 11564 , Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8070-2525","authenticated-orcid":false,"given":"Muriel","family":"Desbois","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA 98101 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domni\u0163a-Valeria","family":"Rusnac","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington School of Medicine , Seattle, WA 98195 , USA"},{"name":"Howard Hughes Medical Institute, Department of Pharmacology, University of Washington , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raashda A","family":"Sulaiman","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, King Faisal Specialist Hospital and Research Center , Riyadh 11564 , Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Lalani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"Murdock","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay C","family":"Burrage","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping Yee","family":"Billie Au","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Alberta Children\u2019s Hospital Research Institute, Cumming School of Medicine, University of Calgary , Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelley","family":"Towner","sequence":"additional","affiliation":[{"name":"Pediatric Genetics, University of Virginia , Charlottesville, VA 22903 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G","family":"Wilson","sequence":"additional","affiliation":[{"name":"Pediatric Genetics, University of Virginia , Charlottesville, VA 22903 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Genetics, Northern California Kaiser Permanente , Oakland, CA 94611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5183-780X","authenticated-orcid":false,"given":"Theresa","family":"Brunet","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich , 81675 Munich , Germany"},{"name":"Institute of Neurogenomics (ING), Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health , 85764 Neuherberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gertrud","family":"Strobl-Wildemann","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, MVZ Humangenetik Ulm , 89073 Ulm , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E","family":"Burton","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Illinois College of Medicine at Peoria , Peoria, IL 61605 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Hoganson","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Illinois College of Medicine at Peoria , Peoria, IL 61605 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"McWalter","sequence":"additional","affiliation":[{"name":"Genedx, Inc. , 207 Perry Parkway, Gaithersburg, MD 20877 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Begtrup","sequence":"additional","affiliation":[{"name":"Genedx, Inc. , 207 Perry Parkway, Gaithersburg, MD 20877 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri A","family":"Zarate","sequence":"additional","affiliation":[{"name":"Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences , Little Rock, AR 72202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elyse L","family":"Christensen","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA 98101 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla J","family":"Opperman","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA 98101 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C","family":"Giles","sequence":"additional","affiliation":[{"name":"Division of Medical Sciences, University of Northern British Columbia , Prince George, BC V2N 4Z9 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Helaby","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center , Riyadh 11564 , Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Kania","sequence":"additional","affiliation":[{"name":"Institut de recherches cliniques de Montr\u00e9al (IRCM) , Montr\u00e9al, QC H2W 1R7 , Canada"},{"name":"Integrated Program in Neuroscience, McGill University , Montr\u00e9al, QC H3A 2B4 , Canada"},{"name":"Division of Experimental Medicine, McGill University , Montr\u00e9al, QC H3A 2B2 , Canada"},{"name":"Department of Anatomy and Cell Biology, McGill University , Montr\u00e9al, QC H3A 0C7 , 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Basic findings reaffirmed","volume":"117","author":"Seymour","year":"1994","journal-title":"Brain"},{"key":"2023070503272354300_awac364-B3","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nrn1723","article-title":"Forty-five years of split-brain research and still going strong","volume":"6","author":"Gazzaniga","year":"2005","journal-title":"Nat Rev Neurosci"},{"key":"2023070503272354300_awac364-B4","doi-asserted-by":"crossref","first-page":"e39804","DOI":"10.1371\/journal.pone.0039804","article-title":"The role of corpus callosum development in functional connectivity and cognitive processing","volume":"7","author":"Hinkley","year":"2012","journal-title":"PLoS One"},{"key":"2023070503272354300_awac364-B5","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/0028-3932(81)90074-9","article-title":"Interhemispheric integration of sensory and motor functions in agenesis of the corpus 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