Center for Medical Ethics and Health Policy Staff Publications
Publication Date
7-1-2024
Journal
Genetics in Medicine
DOI
10.1016/j.gim.2024.101141
PMID
38629401
PMCID
PMC11232373
PubMedCentral® Posted Date
7-9-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Humans, Phenotype, Animals, Mice, Genetic Diseases, Inborn, Genes, Lethal, Databases, Genetic, Disease Models, Animal, Genes, Essential, Mendelian disorders, Lethal phenotypes, Essential genes, Novel gene discovery, Lethal mouse knockouts
Abstract
Purpose: Existing resources that characterize the essentiality status of genes are based on either proliferation assessment in human cell lines, viability evaluation in mouse knockouts, or constraint metrics derived from human population sequencing studies. Several repositories document phenotypic annotations for rare disorders; however, there is a lack of comprehensive reporting on lethal phenotypes.
Methods: We queried Online Mendelian Inheritance in Man for terms related to lethality and classified all Mendelian genes according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. We characterized the genes across these lethality categories, examined the evidence on viability from mouse models and explored how this information could be used for novel gene discovery.
Results: We developed the Lethal Phenotypes Portal to showcase this curated catalog of human essential genes. Differences in the mode of inheritance, physiological systems affected, and disease class were found for genes in different lethality categories, as well as discrepancies between the lethal phenotypes observed in mouse and human.
Conclusion: We anticipate that this resource will aid clinicians in the diagnosis of early lethal conditions and assist researchers in investigating the properties that make these genes essential for human development.