Overall, there was a great diversity in the contribution of LoF and missense variants to the mutational load across genes (Figures 5C–5E and S4). Of all the LoF variants, the fraction contributing to the P/LP group was highest for genes for which haploinsufficiency is the mechanism of action (autosomal-dominant and X-linked genes) such as EYA1, TCOF1, SOX10, and GATA3 (Figure 5C). This trend was further accentuated when assessing the contribution of LoF variants to the mutational spectrum of these genes (Figure 5E). For example, LoF mutations in TCOF1 and EYA1 represent ∼90% and 80% of all reported pathogenic variants, respectively.