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Current prenatal and pediatric genetic evaluation requires three tests to capture balanced chromosomal abnormalities (karyotype), copy number variants (microarray), and coding variants (whole exome sequencing [WES] or targeted gene panels). Here, we explored the sensitivity, specificity, and added value of whole genome sequencing (WGS) to displace all three conventional approaches. We analyzed single nucleotide variants, small insertions and deletions, and structural variants from WGS in 1,612 autism spectrum disorder (ASD) quartet families (n=6,448 individuals) to benchmark the diagnostic performance of WGS against microarray and WES. We then applied these WGS variant discovery and interpretation pipelines to 175 trios (n=525 individuals) with a fetal structural anomaly (FSA) detected on ultrasound and pre-screened by karyotype and microarray. Analyses of WGS in ASD quartets identified a diagnostic variant in 7.5% of ASD probands compared to 1.1% of unaffected siblings (odds ratio=7.5; 95% confidence interval=4.5-13.6; P=2.8x10-21). We found that WGS captured all diagnostic variants detected by microarray and WES as well as five additional diagnoses, reflecting a 0.3% added yield over WES and microarray when combined. The WGS diagnostic yield was also inversely correlated with ASD proband IQ. Implementation in FSA trios identified a diagnostic variant not captured by karyotype or microarray in 12.0% of fetuses. Based on these data and prior studies, we estimate that WGS could provide an overall diagnostic yield of 47.6% in unscreened FSA referrals. We observed that WGS was sensitive to the detection of all classes of pathogenic variation captured by three conventional tests. Moreover, diagnostic yields from WGS were superior to any individual genetic test, warranting further evaluation as a first-tier diagnostic approach. ### Competing Interest Statement The authors have declared no competing interest.

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