RareBoost: A Research-Integrated Program for Rare and Undiagnosed Diseases in Türkiye

Background Advanced genomic sequencing has improved rare disease (RD) diagnostics, yet many patients remain undiagnosed despite extensive molecular testing. Increasingly, the major challenge lies not in data generation, but in the integration and reinterpretation of clinical and genomic information over time. Here, we describe RareBoost (RB), a research-integrated framework for unresolved RDs based on coordinated multidisciplinary evaluation and systematic genomic reinterpretation in Türkiye. Methods RB established a nationwide multidisciplinary diagnostic program for patients with unresolved RDs, integrating expertise in clinical genetics, molecular biology, and bioinformatics through a monthly advisory board. Most enrolled cases had remained unsolved despite prior extensive evaluations, frequently including whole-exome sequencing (WES). The RB workflow included deep phenotyping, reanalysis of prior genomic data, trio-based whole-genome sequencing (WGS), and complementary transcriptomic or functional investigations when indicated. Results The RB registry includes 1,057 individuals from 385 families, of whom 201 completed the diagnostic workflow. A definitive molecular diagnosis was established in 27.4% of cases, while clinically relevant variants of uncertain significance were identified in an additional 32.3%. Reanalysis of prior WES data alone resolved a subset of cases without additional sequencing. In unresolved WES-negative cases, WGS identified additional pathogenic findings, including deep intronic and structural variants. Diagnostic resolution was achieved through iterative reinterpretation within a longitudinal multidisciplinary framework. Conclusions Many unresolved RD cases benefit from systematic reinterpretation of existing genomic data within structured multidisciplinary systems. Our findings suggest that real-world diagnostic limitations increasingly arise not only from sequencing access, but from fragmentation of clinical and genomic interpretation processes over time. The RB framework supports a shift from one-time testing to integrated, iterative diagnostic models for unresolved RDs.