Lethal phenotypes in Mendelian disorders

Abstract

Essential genes are those whose function is required for cell proliferation and/or organism survival. A gene's intolerance to loss-of-function can be allocated within a spectrum, as opposed to being considered a binary feature, since this function might be essential at different stages of development, genetic backgrounds or other contexts. Existing resources that collect and characterise the essentiality status of genes are based on either proliferation assessment in human cell lines, embryonic and postnatal viability evaluation in different model organisms, and gene metrics such as intolerance to variation scores derived from human population sequencing studies. There are also several repositories available that document phenotypic annotations for rare disorders in humans such as the Online Mendelian Inheritance in Man (OMIM) and the Human Phenotype Ontology (HPO) knowledgebases. This raises the prospect of being able to use clinical data, including lethality as the most severe phenotypic manifestation, to further our characterisation of gene essentiality. Here we queried OMIM for terms related to lethality and classified all Mendelian genes into categories, according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. To showcase this curated catalogue of human essential genes, we developed the Lethal Phenotypes Portal (https://lethalphenotypes.research.its.qmul.ac.uk), where we also explore the relationships between these lethality categories, constraint metrics and viability in cell lines and mouse. Further analysis of the genes in these categories reveals differences in the mode of inheritance of the associated disorders, physiological systems affected and disease class. We highlight how the phenotypic similarity between genes in the same lethality category combined with gene family/group information can be used for novel disease gene discovery. Finally, we explore the overlaps and discrepancies between the lethal phenotypes observed in mouse and human and discuss potential explanations that include differences in transcriptional regulation, functional compensation and molecular disease mechanisms. 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.

Improving prenatal diagnosis through standards and aggregation

“…Furthermore, there is an effort to create a catalog of lethal phenotypes in humans, including curation and collation of the (earliest) age of death reported for known Mendelian disorders. 90 In its current version (2023-09-27), it contains 959 genes associated with prenatal, neonatal, or infancy death based on Online Mendelian Inheritance in Man clinical records. Additional integration of both validated and candidate variants/genes identified through sequencing studies of pregnancy loss, fetal and perinatal lethal manifestations, may reveal novel disease-associated genes along with expansions of the clinical spectrum for known Mendelian genes.…”