It has been estimated that at least 6.0% of neonates admitted to the Neonatal Intensive Care Unit remains genetically undiagnosed because genetic testing is not routinely performed. The objective of this study is to provide an overview of average healthcare costs for patients admitted to the Neonatal Intensive Care Unit and to assess possible impact of implementing Whole Exome Sequencing (WES) on these total healthcare costs. Hereto, we retrospectively collected postnatal healthcare data of all patients admitted to the level IV Neonatal Intensive Care Unit at the Radboudumc (October 2013–October 2015) and linked unit costs to these healthcare consumptions. Average healthcare costs were calculated and a distinction between patients was made based on performance of genetic tests and the presence of congenital anomalies. Overall, on average €26,627 was spent per patient. Genetic costs accounted for 2.3% of all costs. Healthcare costs were higher for patients with congenital anomalies compared to patients without congenital anomalies. Patients with genetic diagnostics were also more expensive than patients without genetic diagnostics. We next modelled four scenarios based on clinical preselection. First, when performing trio-WES for all patients instead of current diagnostics, overall healthcare costs will increase with 22.2%. Second, performing trio-WES only for patients with multiple congenital anomalies will not result in any cost changes, but this would leave patients with an isolated congenital anomalies untested. We therefore next modelled a scenario performing trio-WES for all patients with congenital anomalies, increasing the average per patient healthcare costs by 5.3%. This will rise to a maximum of 5.5% when also modelling for an extra genetic test for clinically selected patients to establish genetic diagnoses that are undetectable by WES. In conclusion, genetic diagnostic testing accounted for a small fraction of total costs. Implementation of trio-WES as first-tier test for all patients with congenital anomalies will lead to a limited increase in overall healthcare budget, but will facilitate personalized treatments options guided by the diagnoses made.