Lethal Phenotypes Portal
About
The Lethal Phenotypes Portal is a curated online resource containing a catalogue of genes associated to lethal phenotypes in humans. More detailed information regarding the contents of this resource and the methods that were used to collate the information presented here can be found in the 'Database Content' and 'Data Curation' tabs.
Gene summary
Gene based search to display a summary of the information contained on the catalogue. Type the gene symbol in the Search Gene box. For more detailed information and access to the entire catalogue, go to the 'OMIM Catalogue' tab.
Search Gene
Last updated 11.01.2024. For more information please contact us at https://whri-phenogenomics.github.io/
Content of the database
Data Curation
Contains a brief description of the methods used in the data curation process when creating this app. These include the search terms used as part of the OMIM query strategy and subsequent manual curation to identify genes associated to lethal phenotypes in humans, the criteria used to assign genes to different lethality categories, and summary information on the resulting dataset.
OMIM
OMIM Catalogue
Data in tabular format available for download that displays information on all the gene-disease pairs curated from OMIM records, whether they were identifed as lethal hits through our queries or not, the source of evidence (proband versus affected family members), and gene summary information on the presence of lethal phenotypes and the earliest age of death recorded. HPO age of death categories and definitions are also listed here.
HPO
Mouse Evidence
Mouse evidence on lethality/viability for those genes with a one-to-one human ortholog included in the catalogue. Information on lethality from mouse knockout lines as collected by the Mouse Genome Informatics Database (MGI) and the International Mouse Phenotyping Consortium (IMPC, DR 20.1). Human cell proliferation scores from the 'Gene Effect Score' tab are also included to compare essentiality at the cellular level.
IMPC MGI
LOEUF Score
Displays the distribution of gnomAD v4.0 loss-of-function (LoF) observed/expected upper bound fraction (LOEUF) scores.Lower LOEUF values indicate a higher probability of being intolerant to heterozygous LoF variation. A threshold of 0.35 is suggested by the authors.
gnomAD
Shet Score
Displays the distribution of RGC-ME mean Shet scores, a selection coefficient on relative fitness loss due to heterozygous pLOF variation. A suggested shet cutoff > 0.075 can be used to identify highly constrained genes.
Shet publication
Gene Effect Score
Displays the distribution of mean DepMap 23Q4 CRISPR Gene Effect score which were derived from cancer cell lines as part of the Broad Institute's Dependency Map. Lower Gene Effect scores indicate higher essentiality at the cellular level. A threshold of -0.5 was used to categorise genes as 'Cellular Essential' (<-0.5).
DepMapOMIM querying and curation
OMIM Curation
OMIM clinical records were data mined using a series of API queries of terms linked to lethality. The complete list of terms is illustrated in the Figure. Manual curation of all the hits was performed and ambiguous reports of lethality were discarded. Each unique disease-gene association was assigned to a ‘lethality category’ based on the earliest age of death reported, with categories grouped by age ranges defined by the HPO age of death terms described in the OMIM Catalogue tab.
Following the manual curation process and exclusion of ambiguous entries from OMIM, 57% (2,133/3,773) of genes associated with a subset of OMIM disorders: single-gene,with strict Mendelian phenotypes and molecular basis known were not captured by the queries. This indicates a lack of clinical records pertaining to lethality. Moreover, 33% (1,239/3,773) are exclusively linked to disorders that have documented lethal phenotypes. The remaining 11% (401/3,773) are associated with both lethal and non-lethal phenotypes. In terms of lethality categories, 975 genes (59% of all lethal genes, 26% of all disease genes catalogued), have records of prenatal, neonatal or infant death (classified as pre-infant-lethal) as opposed to post-infant-lethal genes, where the earliest reported age of death spans from childhood to adulthood.
*Non lethal means no records of early death in OMIM OR not captured by our OMIM API queries.
![](catalogue_omim.jpg)
Catalogue of lethal phenotypes in humans curated from OMIM
This catalogue of genes was curated from OMIM, identifying reports of lethality through different fields including 'Description', 'Clinical Synopsis' and 'Clinical Features'. The entire list of search terms can be found in the 'Data Curation' tab. We have included all disorders with specific mention to a lethal phenotype and assigned each gene-disorder to one of seven lethality categories according to the earliest age at which death occured according to OMIM records. The age brackets for these categories are based on definitions provided by Human Phenotype Ontology (HPO) terms. The details for these categories are listed below:
Lethality categories according to HPO:
- L1: Prenatal death (HP:0034241); Death before birth
- L1.1: Miscariage (HP:0005268); Spontaneous loss of a fetus before the 22th week of pregnancy
- L1.2: Stillbirth (HP:0003826); Death of the fetus in utero after at least 22 weeks of gestation
- L2: Neonatal death (HP:0003811); Death within the first 28 days of life
- L3: Death in infancy (HP:0001522); Death within the first 24 months of life
- L4: Death in childhood (HP:0003819); Death during childhood, defined here as between the ages of 2 and 10 years
- L5: Death in adolescence (HP:0011421); Death during adolescence, the period between childhood and adulthood (roughly between the ages of 10 and 19 years)
- L6: Death in adulthood (HP:0033763); Cessation of life at the age of 16 years or later
- LU: Age of death undetermined
For multiple search terms, use '|' between the words, e.g. syndrome|demise
Mouse Evidence for Pre-infant lethal genes
Mouse viability data was obtained from two different sources of evidence: 1) Primary viability screen performed on knockout lines by the International Mouse Phenotyping Consortium (IMPC), and 2) Evidence of lethal phenotypes in knockout mouse as collected from the literature in the Mouse Genomes Informatics (MGI) resource.
Mouse Evidence for OMIM Catalogue genes
MGI
IMPC
LOEUF Comparisons
The histograms and violin plots show the distribution of gnomAD's loss-of-function (LoF) observed/expected upper bound fraction (LOEUF) scores. Lower LOEUF values indicate a higher probability of being intolerant to heterozygous LoF variation. A threshold LOEUF < 0.35 is suggested by the authors to identify constrained genes. The dropdown menu allows the selection of different lethality categories and modes of inheritance for comparison.
Shet Comparisons
The histograms and violin plots show the distribution of RGC-ME mean Shet score, a selection coefficient on relative fitness loss due to heterozygous pLOF variation. A suggested shet cutoff shet > 0.075 can be used to identify highly constrained genes. The dropdown menu allows the selection of different lethality categories and modes of inheritance for comparison.
DepMap Comparisons