Economic and diagnostic impact of adopting WES and WGS as first-tier tests in the paediatric rare disease diagnosis: evidence from Italy and Spain

Abstract Background Whole-Exome Sequencing (WES) and Whole-Genome Sequencing (WGS) can improve the diagnostic journey of paediatric patients with rare diseases by reducing the ‘diagnostic odyssey’ and increasing diagnostic yield (DY). However, the economic impact of implementing these technologies as first-tier tests in clinical practice and the identification of the most appropriate strategy for different patient types remain unclear. Methods We performed a micro-costing analysis in three European centres of excellence for rare diseases to estimate DY, total diagnostic pathway costs, and cost per diagnosed patient across different diagnostic scenarios for two patient groups: critically ill inpatients and outpatients with neurodevelopmental delays. Results For inpatients, first-tier WGS was projected to reduce costs per diagnosed patient by 85–98% (€251,656- €1,968,669 savings per diagnosis), compared with sequential genetic testing, mainly due to shorter neonatal intensive care unit stays until the diagnostic endpoint. For outpatients, first-tier WGS produced the lowest expected cost per diagnosis in one of three centres, reducing costs per diagnosed patient by 57% (€11,258 savings per diagnosis), compared with last-tier use or use of large clinical panels. In the remaining two centres, the most convenient strategy was first-tier WES, reducing costs per diagnosed patient by 9–46% (€762-€3,579 savings per diagnosis). Conclusions These findings support a stratified first-tier sequencing approach in which WGS is prioritised for critically ill inpatients due to its superior clinical and economic value, while WES remains a pragmatic and cost-effective first-tier option for many outpatient pathways. As sequencing costs continue to decline and analytical capabilities expand, WGS is expected to become increasingly advantageous across settings.