Based on our multidisciplinary and complementary expertise around NGS, our pioneering work for diagnostic application of NGS (gene panels and exomes) and access to all genetic patient cohorts in a national consortium (including all clinical genetic centres in the Netherlands), we will develop personalized care pathways for rare disease through involvement of all relevant stakeholders. Using a multidimensional model of clinical utility,10 we will provide for the first time evidence on the utility and cost-effectiveness of a (rapid) WGS-first care pathway. Clinical validity of WGS and rapid genetic testing (by WES) has been demonstrated sufficiently2,7,8. For instance, evidence of effectiveness for NGS-based testing has been unarguably been demonstrated by an increase in diagnostic yield for rare Mendelian disorders, ID and other clinical and genetic heterogeneous disorders2,3,5,11-16. Moreover, more accurate therapeutic interventions were offered in 18% who obtained a diagnosis3 and changes in clinical care were reported in 49% of newly diagnosed families.8 It was furthermore noticed that if NGS had been the first tier genetic test –performed at symptom onset– time to diagnosis (TTD) would have been reduced by 77 months.8 It is needless to say that a TTD of >6.5 years is unsatisfactory for NND patients, but unacceptable for critically ill newborns given that patient outcome may depend on treatment options instilled by a genetic diagnosis, subsequently lessening morbidity and mortality.7,17 To assess the clinical utility of a (rapid) WGS-first approach, we propose a prospective parallel study design (PPD) in which patients receive both the standard diagnostic pathway as well as the WGS-first pathway. For NICU patients, the WGS-first will be assessed as instant test. Our PPD allows us to directly compare the outcome measures, including diagnostic yield and costs associated with each pathway, not biased by the clinical heterogeneity of the study cohort itself.