title: Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice.
abstract: Background: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.Methods: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.Results: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.Conclusions: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.
authors.affiliation: The Francis Crick Institute, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Division of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, Austria.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Geyer
authors.affiliation: Division of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, Austria.
authors.forename: Lukas
authors.identifier: 0000-0001-5833-8176
authors.initials: L
authors.lastname: Reissig
authors.affiliation: Division of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Rose
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Dorota
authors.initials: D
authors.lastname: Szumska
authors.affiliation: The Francis Crick Institute, London, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Hardman
authors.affiliation: The Francis Crick Institute, London, UK.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Prin
authors.affiliation: The Francis Crick Institute, London, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: McGuire
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Ramirez-Solis
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Jacqui
authors.initials: J
authors.lastname: White
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galli
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tudor
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tuck
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Cecilia Icoresi
authors.initials: CI
authors.lastname: Mazzeo
authors.affiliation: The Francis Crick Institute, London, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Robertson
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: David J
authors.identifier: 0000-0001-9490-0306
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: The Francis Crick Institute, London, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Mohun
authors.affiliation: Division of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Wien, Austria.
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Weninger
keywords: development; embryo; high-resolution episcopic microscopy; morphology; mouse; penetrance; phenotype