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

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 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

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

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

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).

DepMap

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.