ArticleGenome medicine2022
Mendelian gene identification through mouse embryo viability screening.
Article in Genome medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- International Mouse Phenotyping Consortium Portal: facilitating investigation of gene function and providing insights into human disease.Nucleic acids research · 2026Article
- Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT).Environmental and molecular mutagenesis · 2025Review
- International Mouse Phenotyping Consortium: Investigating gene function and providing insights into human disease.bioRxiv : the preprint server for biology · 2025Article
- Commentary: The International Mouse Phenotyping Consortium: high-throughput in vivo functional annotation of the mammalian genome.Mammalian genome : official journal of the International Mammalian Genome Society · 2024Article
- Impact of essential genes on the success of genome editing experiments generating 3313 new genetically engineered mouse lines.Scientific reports · 2024Article
- Lethal phenotypes in Mendelian disorders.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Machine learning in time-lapse imaging to differentiate embryos from young vs old mice†.Biology of reproduction · 2024Article
- Computational identification of disease models through cross-species phenotype comparison.Disease models & mechanisms · 2024Article
- Lethal phenotypes in Mendelian disorders.medRxiv : the preprint server for health sciences · 2024Article
- Essential genes: a cross-species perspective.Mammalian genome : official journal of the International Mammalian Genome Society · 2023Review
- Mendelian gene identification through mouse embryo viability screening.Genome medicine · 2022Article
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Authors and funding
33 authors.
Funding
Abstract
backgroundThe diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property.
methodsHere we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project.
resultsWe found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts.
conclusionsInformation on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.
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