This study reports the systematic characterization of embryonic lethal phenotypes as part of the International Mouse Phenotyping Consortium (IMPC) effort to generate a genome-wide catalogue of gene function. Using a standardized, high-throughput pipeline, the authors identified novel phenotypes for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. The analysis revealed that incomplete penetrance and variable expressivity are common, even on a defined genetic background. The study also found that human disease genes are enriched among essential genes identified in the screen, providing a novel dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts. The IMPC effort expanded the phenotypic spectrum for over 300 genes associated with known Mendelian diseases and identified novel human disease candidates. The high-resolution, high-throughput 3D imaging methods used in this study provided detailed morphological information and automated analysis, contributing to a rich resource with significant relevance to disease-causative genes in humans.This study reports the systematic characterization of embryonic lethal phenotypes as part of the International Mouse Phenotyping Consortium (IMPC) effort to generate a genome-wide catalogue of gene function. Using a standardized, high-throughput pipeline, the authors identified novel phenotypes for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. The analysis revealed that incomplete penetrance and variable expressivity are common, even on a defined genetic background. The study also found that human disease genes are enriched among essential genes identified in the screen, providing a novel dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts. The IMPC effort expanded the phenotypic spectrum for over 300 genes associated with known Mendelian diseases and identified novel human disease candidates. The high-resolution, high-throughput 3D imaging methods used in this study provided detailed morphological information and automated analysis, contributing to a rich resource with significant relevance to disease-causative genes in humans.