Fig. 4

Platform comparisons for DNM detection. a Rate of exonic DNMs reported across six WGS and WES studies [6,7,8, 10, 136, 137]. The transition to WGS has generally led to marked improvements in estimates of the average number of DNMs per exome, although improved methodology has also facilitated better DNM estimates for WES. Although the 2017 DDD study used improved DNM calling estimates, they also applied more permissive calling criteria for DNMs than the other WES studies to improve sensitivity. For example, 15% of individuals in the DDD study carry four or more DNMs, accounting for 31% of the DNMs reported in the study, with some individuals carrying as many as 36 DNMs per exome. b Rate of genomic CNVs reported across four SNP microarray and WGS studies [8, 24, 26, 138]. WGS resulted in a noticeable increase in the average number of de novo CNVs per genome due to the improved resolution to detect smaller (< 1 kbp) CNVs. c Relationship between the number of DNMs per child and father’s age at birth (blue dots) for 986 individuals from a recent study of autism (reproduced with permission from [8]). The estimated rate of increase in DNMs per year of paternal age (black line) is 1.64 (95% CI 1.48–1.81) [8]. d Venn diagram comparing DNM yield for WGS and WES from a recent study of 516 autism families (reproduced with permission from [8]). Validation rates (VR) and number of DNMs tested are listed for WGS only, WES only, or both. DNMs discovered by WGS only or both have higher VRs than WES-only DNMs, likely due to more uniform coverage of the exome by WGS. e Venn diagram comparing yield for de novo CNVs between WGS and WES from a recent study of 53 ASD families (reproduced with permission from [53]). Average CNV size was 10 ± 24 kbp (WGS) and 38 ± 64 kbp (WES) and median was 2 kbp (WGS) and 7 kbp (WES). De novo CNVs discovered by both WGS and WES had higher VRs than for de novo CNVs discovered by WGS. None of the de novo CNVs discovered by WES alone were validated. CNV copy number variant, DD developmental delay, DDD deciphering developmental disorders, DNM de novo mutation, SNP single-nucleotide polymorphism, VR validation rate, WES whole-exome sequencing, WGS whole-genome sequencing