OBJECTIVES:  Primary objective of this research is to assess and quantify the total costs of a genetic diagnosis for children suspected for intellectual disability (ID). Secondary objective is to identify the impact of genetic testing on medical decision-making and costs in the future. METHODS:  We retrospectively analyzed medical records of 371 young patients who have undergone WES at various stages of their diagnostic odyssey. Complete resource use data were collected at the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. We categorized the young patients according to their WES-based diagnosis (yes, no, and uncertain), and assessed the per-patient healthcare activities and corresponding costs before (PRE) and after (POST) the diagnosis was obtained. RESULTS: In the cohort of 371 patients, 129 patients received a genetic diagnosis (35%). In 89 (24%) patients no mutation was identified and 153 patients (41%) had an uncertain (variant-of-unknown-significance) diagnosis. We estimated implementation of WES-first would result in mean savings of €5122 euro per patient resulting from replacement of all other genetic technologies and 50% of non-genetic diagnostic tools and consults. A decrease in costs was observed in the majority of categories POST-WES, only the costs of consults in all categories and the costs of genetic tests after not having a diagnosis (+300%) increased. CONCLUSIONS:  Our study confirms that WES is a cost-effective replacement of traditional diagnostic technologies for patients with ID. Looking at the high, although similar in all WES-based diagnostic groups, costs WES could be a cost-efficient and unique option when implemented early in patient care: it could reduce health care costs and induce the amount of distinct diagnoses. On the other hand, our data demonstrate that for patients not having a diagnosis the diagnostic costs have increased after WES. This indicates a change in mindset is needed when implementing WES on a broad scale.