Clinical application of whole-exome and whole-genome sequencing (WES and WGS) has led to an increasing interest in how it could drive healthcare decisions. As with any healthcare innovation, implementation of next-generation sequencing in the clinic raises questions on affordability and costing impact for society as a whole. We retrospectively analyzed medical records of 370 patients with ID who had undergone WES at various stages of their diagnostic trajectory. We collected all medical interventions performed on these patients at the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. We categorized the patients according to their WES-based preliminary diagnosis ("yes", "no", and "uncertain"), and assessed the per-patient healthcare activities and corresponding costs before (pre) and after (post) genetic diagnosis. The WES-specific diagnostic yield among the 370 patients was 35% (128 patients). Pre-WES costs were €7.225 on average. Highest average costs were observed for laboratory-based tests, including genetics, followed by consults. Compared to pre-WES costs, the post-WES costs were on average 80% lower per patient, irrespective of the WES-based diagnostic outcome. Application of WES results in a considerable reduction of healthcare costs, not just in current settings, but even more so when applied earlier in the diagnostic trajectory (genetics-first). In such context, WES may replace less cost-effective traditional technologies without compromising the diagnostic yield. Moreover, WES appears to harbor an intrinsic "end-of-trajectory" effect; regardless of the diagnosis, downstream medical interventions decrease substantially in both number and costs.