A newly published review, Advancing the diagnosis of rare neuromuscular and neurological diseases through the collaborative Solve-RD research framework, reflects on one of Europe's largest collaborative efforts to improve the diagnosis of rare diseases through systematic genomic reanalysis.
Rather than focusing on generating new sequencing data alone, the review highlights a simple but powerful idea: genomic data continue to gain value over time. As disease knowledge expands, analytical methods improve, and new technologies become available, datasets that once yielded no diagnosis can help “solve families” - that is, identify the genetic cause of disease in families who had previously remained without an answer - years after they were first generated. It is a compelling reminder that the diagnostic journey does not necessarily end with an initial negative result.
Solve-RD: a collaborative approach to unsolved rare diseases
Launched in 2018, Solve-RD brought together clinicians, researchers and data scientists across Europe to systematically revisit genomic data from patients with previously unsolved rare diseases. By combining expertise across the European Reference Networks (ERNs) with complementary approaches such as RNA sequencing and other multi-omics technologies, the consortium created a framework for large-scale collaborative reanalysis.
The results demonstrate the value of this approach. In one of the consortium's largest studies, 506 of more than 6,000 previously unsolved families received a genetic diagnosis through systematic reanalysis, as reported in the consortium's flagship Nature Medicine publication.
More recently, a complementary RNA sequencing study released in MedRxiv provided diagnoses for 19 of 248 families whose DNA analyses had previously been inconclusive, while also identifying several novel candidate disease genes.
From archived data to new diagnoses
These achievements depended on more than new analytical methods—they relied on the continued availability of genomic data.
Throughout the Solve-RD project, datasets were securely archived at the European Genome-phenome Archive (EGA), enabling long-term preservation and controlled access for future research and reanalysis. More than 750,000 files, representing over 800 TB of data, were deposited in the archive. Today, the Solve-RD collection remains the second largest collection of datasets at the EGA and discoverable under study EGAS00001003851, allowing authorised researchers to request access through the project's Data Access Committee.
Looking ahead
While the review reflects on the achievements of Solve-RD, its message extends beyond a single project. It shows how systematic reanalysis, collaborative interpretation and the responsible reuse of existing data can continue generating diagnoses long after those data were first produced.
Building on the collaborative foundations established through RD-Connect, Solve-RD and EJP RD, the European Rare Diseases Research Alliance (ERDERA) is now expanding this model across Europe. ERDERA has already brought together 10,000 harmonised genomic and phenotypic datasets from unsolved rare disease cases into a secure European resource, with the long-term ambition of integrating 100,000 genomic and multi-omics datasets to accelerate rare disease research and diagnosis.
The EGA is actively working with ERDERA partners to support the operation of this large-scale effort: from aiding in coordinating and processing data submissions to enabling their secure archival and controlled reuse. This support extends across genomic, transcriptomic and other multi-omics data, including emerging technologies such as long-read sequencing, optical genome mapping and novel omics approaches. By helping centres submit and manage increasingly diverse datasets at scale, the EGA supports their integration into a sustainable resource that can be revisited as technologies evolve and new research questions emerge.
