Hematological genes and variants. (A) Genome positions of the variant-containing genes in the study cohort on genome ideogram^61,62  indicating positions of the 56 study genes with variants (red) and the two major HHT genes ACVRL1 and ENG. Variants present in patients with an identified variant in HHT genes are indicated for ACVRL1 (purple lines) and ENG (blue lines). To preserve anonymity, data for the single SMAD4, GDF2, and EPHB4 families are not illustrated. (B) Chromosomal distributions of variant-containing genes per 100 Mb of gDNA (blue circles/lines), number of variants per Mb (red shaded background), and variants with CADD score >15 (red circles/lines) per Mb of gDNA by chromosome.⁴⁹  (C) Population-level burden of genetic damage in the 6 HHT panel genes (blue) and 75 study hematological genes (red), as detailed in supplemental Table 1. The study genes were subcategorized by variant presence (Variant genes; N = 56) and absence (No-variant genes; N = 19) in the study cohort, and P values were calculated by Dunn’s post Kruskal Wallis: (Ci) Gene damage index (GDI) phred scores, a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population that performs well at removing exome variants in genes irrelevant to disease.⁶³  (Cii) Residual variation intolerance scores (RVIS) that perform better for detection of genes in which newly identified variants are more likely cause a recognized disease.⁶⁴