Figure 4: Number of cited variants (NCV) score applied to haploinsufficient disease genes (ClinGen Dosage Sensitivity Project).

For 127 autosomal genes, we annotated each disease-associated gene with its NCV score, for each disease category and classification. Higher NCV scores were associated with (a) earlier age of onset (Mann–Whitney U P = 0.0139), (b) a larger fraction of de novo variants (P = 0.00345), and (c) increased phenotypic severity (P = 0.00494). Box plots range from 25th- to 75th-percentile values, and whiskers include 1.5 times the interquartile range. (d) Genes under the very strongest selection (s_het > 0.3) have lower NCV scores than genes under moderate selection, which may be due to the fact that many of these variants cause such severe effects that they may be less common in clinical cases.