We also utilized our MLE of the number of genes involved in TD risk to predict the likely future gene discovery yield from WES. We fixed the gene number at 420 and varied the cohort size. Therefore, we calculated the number of variants in each iteration based on the cohort size and the observed variant rate per proband. In each iteration, we randomly selected 420 TD risk genes and then assigned a fraction of the permuted variants to these TD risk genes and the leftover fraction to the remaining non-TD risk genes. This allocation was determined based on the fraction of variants estimated to carry risk. We performed 10,000 permutations at each cohort size, separately randomly generating LGD and Mis3 variants, using their observed rates and per-gene likelihoods. These data were then combined, and each permutation was run through the TADA de novo algorithm to assess the per gene q values. We then recorded the number of pTD genes (q < 0.3) and hcTD genes (q < 0.1) observed at each cohort size (Figure 5C). Based on the smoothed curves,
