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Currently, offering whole-exome sequencing (WES) via collaboration with an external laboratory is increasingly common. However, the receipt of a WES report can be merely the beginning of a continuing exploration process rather than the end of the diagnostic odyssey. The laboratory often does not have the information the physician has, and any discrepancies in variant interpretation must be addressed by a medical geneticist. In this study, we performed diagnostic WES of 104 patients with paediatric-onset genetic diseases. The post-exome review of WES reports by the clinical geneticist led to a more comprehensive assessment of variant pathogenicity in 16 cases. The overall diagnostic yield was 41% (n = 43). Among these 43 diagnoses, 51% (22/43) of the pathogenic variants were nucleotide changes that have not been previously reported. The time required for the post-exome review of the WES reports varied, and 26% (n = 27) of the reports required an extensive amount of time (>3 h) for the geneticist to review. In this predominantly Chinese cohort, we highlight the importance of discrepancies between global and ethnic-specific frequencies of a genetic variant that complicate variant interpretation and the significance of post-exome diagnostic modalities in genetic diagnosis using WES. The challenges faced by geneticists in interpreting WES reports are also discussed., Pediatrics: Extra review of exome data boosts diagnostic yield In-depth reviews by clinical geneticists can improve the diagnostic accuracy of exome sequencing data for children with unexplained genetic disorders, especially in non-Western populations that are under-represented in genomic databases. Working with children predominantly of Han Chinese origin, Brian Chung from the University of Hong Kong and coworkers sequenced the entire protein-coding portion of the genome for 104 patients with pediatric-onset genetic disease. Specially trained geneticists analyzed the DNA data to resolve any ambiguous interpretations, link the molecular findings with clinical records, identify ethnic-specific differences and, when necessary, request additional assays. This extra review process was sometimes laborious, taking several hours of the physician’s time, but ultimately led to a more comprehensive assessment in 16 of the 43 diagnoses successfully made. This overall diagnostic yield—41%—was comparable to previous studies in other populations.