What is better as an initial test WES or WGS? A recent paper in the European Journal of Human Genetics put this notion to the test. They found that out of 91 patients across 64 families with undiagnosed Mendelian disorders, in New South Wales, Australia, 13 of the 38 unresolved families (34%) were diagnosed when using WGS instead of WES. Previous WES analyses failed to resolve these cases due to previously unknown gene-disease association (23%), insufficient sequencing coverage (31%), the variant prioritization pipeline (15%), and the bioinformatics pipeline (23%), or CNV detection (8%). Comparing the diagnostic yield over these 64 families revealed a 9% increase in diagnostic yield by using WGS at the outset rather than contemporary WES analysis. As scientific knowledge accumulates both the analysis capabilities improve, hence periodical re-analysis of old unresolved cases might provide a genetical resolution.