Fig. 7. Mutational constraint of genes typically linked with adult cancer (or, biallelically, childhood cancer) risk: shows data regarding the phenotypes associated with monoallelic loss-of-function of classically recessive childhood cancer risk genes.

A Modified adaptation from Kratz et al. (2022)⁸⁵ with permissions provided under the CC BY-NC 4.0 license showing the odds ratio of excess carriers of pathogenic variants (error bars indicate 95% confidence intervals) in children with pan-cancer (discovery cohort; n = 3775 & validation cohort; n = 1664) vs. healthy adults (gnomAD; n = 74,023 & TUM; n = 27,501) for nine classically adult cancer predisposition genes. “Gene-based burden testing was performed and odds ratios, 95% confidence intervals, and P values were calculated using the 2-sided Fisher exact test”⁸⁵. Genes are colored and rearranged according to their loss-of-function observed vs. expected upper bound fraction (LOEUF) score as indicated by the central constraint spectrum bar. On the right exact constraint metrics; loss-of-function observed vs. expected ratio, loss-of-function observed vs. expected lower bound fraction score and LOEUF score, as well as constraint level, are listed. TUM refers to a control cohort of cancer-free individuals sequenced at Technical University of Munich. B The upper tract shows the DIS3L2 loss-of-function variants found in gnomAD v2.1. The lower tract shows the loss-of-function variants found among patients with Wilms tumor (WT) by Hol et al.⁸². Variants are expanded in the upper tract when they overlap with variants in the lower tract. Variant color; orange, nonsense, purple, splice, red, frameshift. Source data are provided as a Source Data file.