OBJECTIVES The primary objective of this study is to elucidate the effect of whole exome sequencing (WES) in diagnosing children with a developmental delay due to unexplained conditions presumed to be genetic. A secondary objective is to collect all resources used by these children to gain insight into the total costs over time for the traditional diagnostic pathway and the additional costs to diagnose a patient using WES. METHODS We included twenty children at the Sylvia Toth Centre (STC) in Utrecht, the Netherlands, who have underwent previously extensive clinical diagnostic workups and for whom no diagnosis was found after the last extensive workup. On all twenty children and parents WES will be performed, thereby obtaining a list of exonic candidate mutations for each patient. In parallel all resources used were collected by assessing the clinical records of patients. These resources were linked to unit costs to obtain the total cost per patient. Total cost per patient was then compared to the cost of care using WES, assessed for each individual patient. RESULTS The diagnostic yield from the 13 patients sequenced thus far is 23% indicating a 23% increase in number of diagnoses compared to the current diagnostic pathway. On average these patients have had numerous visits to the hospital, overnight stays and different diagnostic workups to unravel the genetic cause of their neurological disorder. Total cost of the current diagnostic pathway is therefore up to ten fold higher compared to the total cost of only providing WES. CONCLUSIONS Comparing the diagnosis and costs with and without the use of WES gives a clear picture of the clinical and economic feasibility of putting WES into standard diagnostic practice at the STC and similar genetic centers over the world.