Genetic reanalysis results in more than 500 patients receiving diagnosis

The European consortium for Solving the Unsolved Rare Diseases has demonstrated the significance of international collaboration to address the unmet medical needs for rare diseases’ diagnosis. More than 500 European patients with unknown conditions have received a diagnosis through new genetic research. This includes patients with rare neurological disorders, severe intellectual disabilities, muscle diseases, and hereditary gastrointestinal cancer.

These diagnoses were achieved through extensive European collaboration, led by researchers from the University of Tübingen, Radboud university medical center, and the National Center for Genomic Analysis in Barcelona.

A disease is considered rare in the European Union, if fewer than five out of 10,000 people have the condition. Of the 7,000 rare diseases, at least 70% have a genetic cause. Because these diseases are so rare, it’s difficult to pinpoint the exact cause in the DNA, even when multiple members of one family have the condition.

Researchers have now been able to diagnose a number of European patients and families with their rare genetic disease. These include rare neurological disorders, malformation syndromes and intellectual disabilities, rare neuromuscular diseases, and suspected hereditary cancer risk syndromes.

In total, the researchers reanalyzed the existing genome data of 6,447 patients and 3,197 unaffected family members. Thanks to this research, 506 patients and their families received a diagnosis. For 15% of the patients, there are leads for actionability, in some including treatment; in other cases, the diagnosis provides clarity for the patients and their families.

These results have been published in Nature Medicine.

These diagnoses were made possible by Solve-RD, a large European collaboration involving 300 experts from 12 European countries and Canada. Led by researchers from the University of Tübingen, Radboud university medical center, and the National Center for Genomic Analysis (CNAG) in Barcelona, these experts conducted a thorough reanalysis of patients’ genetic data. They work within European Reference Networks (ERNs) that focus on specific rare diseases.

Thanks to this framework, it no longer matters whether a patient with a rare condition is seen in the Netherlands, Germany, or France. The method for reaching a diagnosis is now the same everywhere. This did not happen easily.

The experts had to agree 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.

Blueprint

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 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 disease 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. This includes scaling up patient data reanalysis from 10,000 to over 100,000 rare disease datasets, and covering a wider range of rare genetic conditions.

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.

Holm Graessner, 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.”

Lisenka Vissers, Professor of 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 for a patient who has been ill for 20 years and has participated in many studies.”

Alexander Hoischen, Professor of Genomic technologies for immune-mediated and infectious diseases and lead researcher from Radboudumcsaid, “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.”