Fig. 4: Developmental disorders gene candidate prioritisation.
From: Human and mouse essentiality screens as a resource for disease gene discovery
a Venn diagram showing the overlap between DL prioritised genes with evidence from 3 large-scale sequencing programmes. Overlap between the set of 163 developmental genes highly intolerant to LoF variation (pLI > 0.90 or o/e LoF upper bound < 0.35 or HI < 10) and not yet associated with disease and the set of candidate genes from three large rare disease sequencing consortia: 100KGP, CMG, and DDD. b Set of nine candidate genes. The selected genes met the following criteria: (1) evidence from both the 100KGP (with detailed clinical phenotypes and variants) and either DDD (variants and high-level phenotypes available) or CMG (gene and high-level phenotypes available), (2) the associated variants were not present in gnomAD, and (3) intolerance to missense variation; these genes were further prioritised based on the number of unrelated probands and the phenotypic similarity between them and the existence of a mouse knockout line with embryo and adult phenotypes that mimic the clinical phenotypes. c Mouse evidence for VPS4A. IMPC embryonic phenotyping of homozygous mutants at E18.5 showed abnormal/curved spine and abnormal brain among other relevant phenotypes. The phenotypic abnormalities observed in heterozygous knockout mice include lens opacity. Heterozygous mouse phenotypic similarity to known disorders as computed by the PhenoDigm algorithm. d Mouse evidence for TMEM63B. IMPC homozygous mouse embryo lacZ imaging at E14.5 supporting neuronal expression during development. Heterozygous IMPC knockout mice associated phenotypes included abnormal behaviour evaluated through different parameters. The heterozygous mice showed a high phenotypic similarity with several developmental disorder phenotypes. VUS variant of unknown significance.
