Within each cohort, we calculated the rates of de novo and inherited mutations per base pair. For accurate rate calculation, we first determined the number of “callable” base pairs per family using the GATK DepthOfCoverage tool. See Supplemental Methods for details. We compared de novo mutation rates in cases versus controls (burden analysis) using a one-tailed rate ratio test in R (https://cran.r-project.org/package=rateratio.test), considering only those variants present with a frequency of <0.01 in the ExAC v0.3.1 database (38). We compared inherited mutation rates in a similar manner but considered only those variants seen once across all cases and controls, and not reported in ExAC. See Supplemental Methods.
