Fig. 4: Many DUBs are intolerant to genomic variation in humans and are likely to cause developmental disease when mutated.

Graph depicting a plot of missense (Z) and loss-of-function intolerance (pLI) scores of all human DUBs (as determined using gnomAD [233]). Highlighted in color are DUBs whose mutations have been demonstrated to cause monogenic diseases that are inherited in an autosomal dominant manner (orange), autosomal recessive manner (green), or X-linked dominant/recessive manner (blue). Mutations in USP8 (highlighted in black) cause corticotroph adenomas and Cushing’s disease in the somatic state. Note that DUBs associated with autosomal dominant and X-linked disease are constrained in their genomic variation within the healthy human population (pLI ≈ 1, Z-score > 1). Many other DUBs, previously not linked to monogenic diseases, are also highly intolerant to missense and loss-of-function mutations and thus likely cause embryonic lethality or developmental disease when mutated. The strongest of these candidates are highlighted in violet in the zoomed-in panel of the plot on the right.