Genetic Reanalysis Provides New Rare Disease Diagnoses

More than 500 European patients with previously undiagnosed rare disorders received a genetic diagnosis through research carried out by an extensive European collaboration, the Solve-Rare Diseases Consortium (Solve-RD), led by researchers from the University of Tübingen, Radboud University Medical Center (Radboudumc), and the National Center for Genomic Analysis in Barcelona. The diagnoses were made in patients with conditions including rare neurological disorders, severe intellectual disabilities, muscle diseases, and hereditary gastrointestinal cancer.

One of the core aims of Solve-RD is to improve the rate of genetic diagnosis for individuals affected by a rare disease. The newly published study in Nature Medicine “Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses,” reported results from the systematic reanalysis of data from 6,004 undiagnosed rare-disease families recruited from across Europe by Solve-RD. The researchers have made their entire dataset available available as a resource for the rare diseases research community worldwide. In their report the team concluded, “The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts.”

Holm Graessner, PhD, Solve-RD coordinator, said “The Solve-RD approach to reanalyze data from unsolved rare disease patients was successful and led to a diagnosis for more than 500 patients. This is a major step forward and a milestone for the rare disease research in Europe. We will continue and scale up this approach in ERDERA to provide a diagnosis to even more patients and families across Europe.”

While the definition of what constitutes a rare disease is “arbitrary, and thus varies by jurisdiction,” the authors noted, in the EU a disease is considered rare if fewer than 5 out of 10,000 people have the condition. More than 70% of the >6,000 unique rare diseases are genetic, the researchers further noted, “… and, collectively, they constitute a major health issue, with 3.5–6.0% of individuals affected by a rare disease over their lifetime.”

Because these diseases are so rare, it’s difficult to pinpoint the exact cause at the DNA level, even when multiple members of one family are affected. The Solve-RD collaboration involves 300 experts from twelve European countries and Canada. The experts conducted a thorough reanalysis of patients’ genetic data. For their research they worked within European Reference Networks (ERNs) that focus on specific rare diseases.

“One of the core aims of Solve-RD is to improve the rate of genetic diagnosis for individuals affected by a rare disease,” the authors noted in their report. “A specific objective of Solve-RD is to systematically collate and reanalyze existing exome/genome datasets and corresponding structured ontology-based phenotype and pedigree information across the disease areas of its ERN partners.”

For the reported study the Solve-RD team reanalyzed the existing genome data of 6,447 European patients and 3,197 unaffected family members. The results of their analyses allowed them to diagnose 506 patients with their genetic rare disease, including those with rare neurological disorders, malformation syndromes and intellectual disabilities, rare neuromuscular diseases, and suspected hereditary cancer risk syndromes.

For nearly 15% of the patients, the results included leads for actionability, including in some potential treatment. In other cases, the diagnosis provided clarity for the patients and their families. “We identified 73 affected individuals (14.4% of diagnosed individuals) that harbored variants in a potentially actionable gene,” the team noted.

Lisenka Vissers, PhD, professor in translational genomics and lead researcher from Radboudumc, said, “We conducted a large reanalysis of an enormous amount of patient data. This allowed us to find similarities and draw conclusions. We have now even been able to provide a diagnosis to a patient who has been ill for twenty years and has participated in many studies.”

Alexander Hoischen, PhD, professor in genomic technologies for immune-mediated and infectious diseases and lead researcher from Radboudumc, added, “The fact that we have achieved this is a unique example of the power of collaboration. It’s a huge step forward in European cooperation, and this is just the beginning. Although we haven’t made any new discoveries yet and these diagnoses come from existing data and analyses, we hope to be able to help many more patients in the coming years. Initially by making a diagnosis, but hopefully also with possible treatments.”

This initiative, based on the Solve-RD project’s two-level expert review framework, provides a structured approach to diagnosing and potentially treating rare diseases. The framework allows analyses to be reviewed by experts from diverse fields, such as clinical genetics and data science, which increases diagnostic accuracy.

The framework means that whether a patient with a rare condition is seen in the Netherlands, Germany, or France is not relevant. The method for reaching a diagnosis is the same everywhere. Setting this framework up required experts agreeing on the analysis method for each condition, for example, which genes and variant types needed to be examined. Logistical challenges and national legislation and regulations were also of major impact.

The approach is being expanded through the European Rare Disease Research Alliance (ERDERA), a new rare diseases partnership coordinated by INSERM, France, with over 180 organizations including key scientists from Solve-RD. Further acceleration of diagnosis of rare diseases patients being one of its goals, by collecting data from a broader pool of patients and collaborating with additional European medical centers, ERDERA aims to offer diagnoses to those who remain undiagnosed, thus scaling the impact of rare disease research.

Within ERDERA, the University of Tübingen leads the Clinical Research Network diagnostic stream, working again alongside teams from Radboudumc, Barcelona and others across Europe. “The tools and infrastructure developed within Solve-RD have been adopted as the core framework for undiagnosed rare-disease case reanalysis within the ERDERA project, which aims to extend out to all 24 ERNs and reanalyze >100,000 datasets from rare-disease families across all disease types,” the team noted.

The work also emphasizes the use of advanced techniques such as long-read genome sequencing, optical genome mapping, and RNA sequencing to accelerate diagnoses for unresolved rare conditions. “To benefit the rare-disease community, our framework will involve expansion to other types of rare diseases through their respective ERNs, the incorporation of novel omics datasets—including those obtained from long-read technologies—and the inclusion of artificial intelligence-based methodology.”

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