Diagnostic pathways in developmental disorders: a decade-apart comparison of two multicenter cohorts (2012–2022)

As part of the third French National Plan for Rare Diseases, the AnDDI-Rares network initiated a nationwide study in 2019 to assess how diagnostic practices for developmental anomalies have evolved over the last decade (2012-2022), in the context of the implementation of genome sequencing (GS) capabilities via the France Genomic Medicine Plan. We analyzed diagnostic rates in 34 French centers for developmental diseases, comparing a randomly selected week in 2012 with one in 2022. Secondary outcomes were diagnostic delays and GS efficiency. A total of 430 patients were identified in 2012 and 551 in 2022, a 28% increase in activity. The overall diagnostic yield rose from 16% in 2012 to 27% in 2022 (p < 0.001), in parallel with the increased use of next-generation sequencing (NGS) approaches, and the shift from targeted gene panels toward GS. Among previously undiagnosed patients from the 2012 cohort who pursued further investigations, NGS enabled additional diagnoses with GS showing a high diagnostic yield (42%) in individuals with longstanding diagnostic odysseys. Significant heterogeneity in strategies persisted, highlighting the impact of, and unequal access to GS across centers. These results highlight advancements in diagnostic practices and the pivotal role of Next-Generation Sequencing. Nonetheless, unequal access, attrition, and limited uptake of renewed investigations reveal persistent barriers. Continuous patient engagement and coordinated efforts are required to promote GS-first approaches and ensure equitable access across the healthcare system.