{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T15:51:17Z","timestamp":1777564277112,"version":"3.51.4"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.9899.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2017,2,27]],"date-time":"2017-02-27T00:00:00Z","timestamp":1488153600000}}],"reference-count":19,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2017,2,27]],"date-time":"2017-02-27T00:00:00Z","timestamp":1488153600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["FC001157"],"award-info":[{"award-number":["FC001157"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["FC001117"],"award-info":[{"award-number":["FC001117"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Trust","award":["100160, 001157, 001117"],"award-info":[{"award-number":["100160, 001157, 001117"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["FC001157, FC001117"],"award-info":[{"award-number":["FC001157, FC001117"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant and 114 wild type embryos from 42 lethal and subviable lines, analysed at E14.5.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    Virtually all mutant embryos show multiple abnormal phenotypes and amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.9899.2","type":"journal-article","created":{"date-parts":[[2017,2,27]],"date-time":"2017-02-27T10:50:09Z","timestamp":1488192609000},"page":"1","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice"],"prefix":"10.12688","volume":"1","author":[{"given":"Robert","family":"Wilson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan 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Icoresi","family":"Mazzeo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2413-9392","authenticated-orcid":false,"given":"James C.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-0306","authenticated-orcid":false,"given":"David J.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Mohun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang J.","family":"Weninger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2017,2,27]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"571-9","DOI":"10.1242\/dmm.011833","article-title":"Bloomsbury report on mouse embryo phenotyping: recommendations from the IMPC workshop on embryonic lethal screening.","volume":"6","author":"D Adams","year":"2013","journal-title":"Dis Model Mech."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"508-514","DOI":"10.1038\/nature19356","article-title":"High-throughput discovery of novel developmental phenotypes.","volume":"537","author":"M Dickinson","year":"2016","journal-title":"Nature."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"562-6","DOI":"10.1242\/dmm.011957","article-title":"Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal 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double-lumen aortic arch malformations.","volume":"196","author":"S Geyer","year":"2012","journal-title":"Cells Tissues Organs."},{"key":"ref-18","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.163506","article-title":"Table 4: All pheotypes from lethal and subviable lines scored by DMDD to date (Nov 2016) [Data set].","author":"R Wilson","year":"2016","journal-title":"Zenodo."},{"key":"ref-19","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.268899","article-title":"Dataset 2: All wild type embryo phenotypes from lethal and sub-viable lines scored by DMDD to date (Nov 2016) [Data set].","author":"R Wilson","year":"2017","journal-title":"Zenodo."}],"container-title":["Wellcome Open 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.10670.r17602, David Brook, School of Life Sciences, University of Nottingham, Nottingham, UK, 05 Dec 2016, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/1-1\/v1#referee-response-17602","order":0,"name":"referee-response-17602","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Tim Mohun<\/b>; \n<i>Posted: 06 Mar 2017<\/i>; The sentence on p4 referenced in the reviewer's comment describes a trend in the similarity of phenotypes across all of the embryos within a particular mutant line. So we are not comparing the phenotypes between lines, but whether there is consistency between different embryos within any individual line.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/1-1\/v2#referee-comment-2539","order":1,"name":"referee-comment-2539","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.11724.r21156, Nadia Rosenthal, National Heart and Lung Institute, Imperial College London, London, UK, 21 Mar 2017, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/1-1\/v2#referee-response-21156","order":2,"name":"referee-response-21156","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.11724.r23596, Lydia Teboul, The Mary Lyon Centre, Medical Research Council Harwell Institute, Didcot, UK, 19 Jun 2017, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/1-1\/v2#referee-response-23596","order":3,"name":"referee-response-23596","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by the Wellcome Trust [100160], [001157], [001117]; Cancer Research UK [FC001157], [FC001117]; and the UK Medical Research Council [FC001157], [FC001117]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}