March 4, 2025 | A transcontinental collaborative effort brought together 300 experts from 12 European countries and Canada to try and crack the genetic cause of thousands of unsolved rare disease cases. Through data-sharing and genetic reanalysis, this “coalition of the willing” has most recently succeeded in providing more than 500 patients with a long-awaited diagnosis—and peace of mind to unaffected family members about whether they carry the risk variant, according to Alexander Hoischen, Ph.D., professor in genomic technologies for immune-mediated and infectious diseases at Radboud university medical center (umc) in the Netherlands.
The consortium, known as Solving the Unsolved Rare Diseases (Solve-RD), involves clinicians, laboratory geneticists, and translational researchers from 43 research groups associated with 37 institutes. Leadership is provided by the University of Tübingen in Germany, which is spearheading the project's overall direction and research strategy, together with Radboudumc and the National Center for Genomic Analysis in Barcelona, Spain.
Answers have come by identifying two or more patients, across geographies, who share the same genetic mutation, Hoischen says. The informative matchmaking exercise is achieved by creatively organizing both expertise and data.
Simply getting Solve-RD up and running was “potentially the biggest achievement,” says Hoischen, noting that it had to accommodate the prevailing laws of multiple countries. The project was funded seven years ago and had its share of skeptics.
The impact of the work is profound and likely underappreciated by many. “If you diagnose a single patient, you can save an entire family,” says Richarda M. de Voer, Ph.D., associate professor at Radboudumc who specializes in familial cancer risk syndromes.
Although a rare disease is defined in the European Union as a condition that affects fewer than 1 in 2,000 people, rare diseases are collectively quite a common healthcare problem, she says. In the world of oncology, very rare patients are in the mix even with commonly occurring cancer types—for example, a 25-year-old who develops colorectal cancer. “I want to figure out why... it’s what drives my research.”
Working on rare genetic diseases is “super gratifying, even for us as biologists, because it is so close to clinical and diagnostic applications,” says Hoischen. It also comes with the satisfaction of having clear-cut answers that are easy to convey to a lay audience; individuals either have a disease and the mutation to explain it or they don’t. With rare genetic diseases, unlike type 2 diabetes and many common cancers, it’s “usually not anything in between.”
Between 70% and 80% of the 7,000 identified rare diseases to date have a known genetic cause. For most of the remainder, the cause is likely genetic but has yet to be discovered, says Hoischen. “We will know in a few years... [when] unexplained diseases are understood in much more detail.”
The genetic causes may well include somatic mutations that accumulate with age, some of which can cause cancer, he says. They can be difficult to detect and may explain why some diseases lack a clear diagnosis. It could turn out that some rare diseases only look like other genetic conditions but are in fact due to exogenous factors such as getting a viral infection during pregnancy or having an adverse reaction to medication.
For cancer predisposition, genetics alone offers an explanation less than 70% of the time, says de Voer. “That might be because there is more interplay between genetics and environmental exposures.”
The Solve-RD initiative has expanded to deep-exome sequencing in the search for somatic mutations, she notes, including somatic variants in cancer as well as for individuals with unsolved rare diseases, such as neuromuscular disease and intellectual disability. Increasingly, experiments and research strategies have been looking through the somatic lens via transcriptomics.
The expansion is happening through the European Rare Disease Research Alliance (ERDERA), a new partnership coordinated by the National Institute for Health and Medical Research (INSERM) in France and involves over 180 organizations with the University of Tübingen leading the Clinical Research Network diagnostic stream. ERDERA will be scaling up patient data reanalysis from 10,000 to over 100,000 rare disease datasets and make greater use of advanced techniques such as long-read genome sequencing, RNA sequencing, and optical genome mapping.
The latest genomic reanalysis exercise of Solve-RD on 6,447 individuals with previously undiagnosed rare diseases from 6,004 families yielded a genetic diagnosis in 506 (8.4%) of families, as reported in Nature Medicine (DOI: 10.1038/s41591-024-03420-w). The method for reaching a diagnosis was the same across multiple national centers comprising four European Reference Networks (ERNs) involved in the pan-European omics project, as well as one collaborating research group in Ontario, Canada.
In 2017, 24 thematic ERNs were created to bring together expertise on rare diseases across the European Union. The ERNs participating in Solve-RD include centers specializing in rare neurological diseases (ERN-RND), intellectual disability, telehealth, and congenital anomalies (ERN-ITHACA), neuromuscular diseases (EURO-NMD), and genetic tumor risk syndromes (ERN-GENTURIS)—where de Voer is heavily involved—as well as the Spanish Undiagnosed Rare Diseases Program.
Solve-RD was funded by the European Commission and that project’s timeframe ended in 2024, says Hoischen, although its work is still in production. A second paper is being prepared for publication that incorporates datasets obtained from long-read genome sequencing (DOI: 10.1101/2024.05.03.24305331). The two papers feature close to 500 patient cases selected for scientific and medical reasons, he adds.
Collaborating centers that didn’t already have long-read technologies were provided with early access. The same will happen with ERDERA, where less privileged countries will be offered the more advanced technologies, Hoischen says.
The primary funder of ERDERA is the European Union, but additional contributions will be needed from member states. Germany and the Netherlands, leaders in long-read genome sequencing, are shoo-ins, says Hoischen. “It may well take longer in other countries... to move from up to 10 different tests to a single one that will make it much more sustainable.”
Actionability of Findings
For about 15% of the 506 families in the latest study, the genetic answer they were given was “potentially actionable,” Hoischen reports. This refers to cases where the causative gene is reported in one of the three gene-treatment databases included in the study (ClinGen, IEMbase and Treatabolome) and in guidelines for surveillance of genetic tumor risk syndromes.
Broadly speaking, actionability would theoretically extend beyond patients having options for treating symptoms or the underlying cause of their disease, he continues, which applied largely to patients having rare neurological or neuromuscular disorders. Family members could also be informed and tested and possibly offered family planning advice regarding recurrence risk.
Overall, the yield for familial cancer risk syndromes was lower (2.8%), says de Voer. This was not unexpected, given that environmental exposures can obscure the genetic link and there may be multiple genes involved.
But in the 10 cases where a causal variant was identified, the entire family benefited. “With a few of the families we diagnosed, we could do segregation analysis to check if the siblings or children had these variants as well,” she says. If so, they were put on a high-frequency cancer screening protocol (e.g., annual or biannual colonoscopies) so that if a tumor develops it gets tackled at an earlier, more treatable stage.
The scientific aspects of what Solve-RD has done are “not exactly rocket science,” says Hoischen. Reanalysis of patients’ genetic data is routinely done at specialized laboratories around the world and has been the basis of published studies, including some by the UK government-owned Genomics England. Several Mendelian disease research centers in the U.S. have also performed genomic reanalysis at either the national or single-center level.
Knowledge about variants and genes is continuously increasing, he says. “We’re nowhere near saturation in our understanding of which genetic defects cause rare genetic diseases.”
The scope of the Solve-RD effort alludes to the inherent struggles in realizing its vision, says Hoischen. Each participating country or center had to arrange for the appropriate consent to join the project and ensure patients were willing to share their data and understood that its exchange on a pan-European level would happen in a safe and viable manner.
A decade ago, some rare disease scientists and doctors would have flatly refused, claiming the patient and data were theirs, he notes. “We had to change their mindset completely... some of these diseases are so rare there may only be one patient in the Netherlands.”
For Hoischen and his Solve-RD colleagues, occasions when they get to contact patients and families with news about a disease’s genetic cause are “the very special days and moments of our careers,” he says. “They express how that has changed their life by having certainty, and in some cases getting better treatment or continued family planning.”
The term “rare diseases is just a misnomer,” he reiterates. Yet many scientists, as well as lay people, continue to underestimate how impactful it is to deliver these rare disease diagnoses.
For more basic scientists like himself, adds Hoischen, “we can learn so much about physiology and the natural role of human genes... and understanding the link between the consequences of variants and aberrant phenotypes.” The lessons learned with this “real human” work extend well beyond their customary research on the fundamental mechanisms and processes within an animal model.