Solving the Unsolved Rare Diseases: Inside the Solve-RD Initiative

By SWA

Solve-RD (Solving the Unsolved Rare Diseases) is a groundbreaking European research initiative funded by the European Union under the Horizon 2020 program. This ambitious project aims to transform the diagnosis of unsolved rare diseases by utilizing advanced genomics, cutting-edge technologies, and the collective expertise of scientists and clinicians from across Europe. Rare diseases, though individually uncommon, affect millions of people worldwide and often remain undiagnosed due to their complexity. Solve-RD is determined to change this.

A Collaborative Force

At its core, Solve-RD is a collaborative effort. The initiative involves over 300 clinicians, laboratory geneticists, and translational researchers from 43 research groups associated with 37 institutes across 12 European countries and Canada. Together, these experts are pooling their resources and knowledge to tackle the challenge of rare diseases that have defied previous diagnostic efforts.

The scale of the initiative is remarkable: the project has collected data from 10,276 genomic datasets, which include 9,722 exomes and 554 genomes. After rigorous quality control measures, the final dataset includes 9,874 genomic datasets representing 6,449 individuals affected by rare diseases and 3,196 unaffected relatives from 6,004 families. This vast repository serves as the foundation for uncovering genetic causes of rare conditions.

Understanding Rare Diseases

" Despite improvements in diagnostics and research options for rare diseases, many individuals remain without a molecularly proven genetic diagnosis" https://www.nature.com/articles/s41591-024-03420-w#Sec2      

A molecularly proven genetic diagnosis refers to the confirmation of a specific genetic condition or disease through molecular genetic testing. This involves identifying a pathogenic (disease-causing) mutation or variation in a gene using techniques such as DNA sequencing, PCR, or other advanced genetic tools. It provides a definitive diagnosis by pinpointing the exact genetic cause of the condition.

Rare diseases are defined as conditions that affect a small percentage of the population, often less than 1 in 2,000 individuals. However, their collective impact is significant, as there are thousands of different rare diseases. Many of these conditions are genetic, and their rarity makes diagnosis particularly challenging. Solve-RD focuses on patients with rare diseases that remain undiagnosed despite thorough clinical and genetic investigations.

The diseases studied in Solve-RD span multiple categories, including:

  • Rare neurological diseases (ERN-RND): 2,271 families
  • Congenital malformations, intellectual disability, and neurodevelopmental disorders (ERN-ITHACA and SpainUDP): 1,857 families
  • Rare neuromuscular diseases (ERN-Euro-NMD): 1,517 families
  • Hereditary gastric and bowel cancers (ERN-GENTURIS): 359 families

Advanced Technologies for Diagnosis

One of the distinguishing features of Solve-RD is its reliance on cutting-edge technologies and methodologies to uncover elusive genetic causes. These include:

  • Whole genome sequencing (WGS) and RNA sequencing to identify complex and novel genetic mechanisms.
  • Multi-omics approaches to study the interaction of genes, proteins, and other molecular factors in rare diseases.
  • Artificial intelligence (AI) and advanced bioinformatics tools to process large datasets, detect rare genetic variants, and uncover diagnostic clues.

By integrating these technologies, Solve-RD can analyze genomic data at an unprecedented scale and depth, paving the way for breakthroughs in diagnosing rare conditions.

A Data-Sharing Revolution

A key principle of Solve-RD is collaboration through data sharing. The initiative uses secure platforms, such as the European Genome-phenome Archive (EGA), to make anonymized datasets available to researchers worldwide. This open approach fosters innovation and allows for the reanalysis of unsolved cases using new tools and techniques.

Additionally, the project utilizes patient registries and biobanks to complement genomic data with clinical information. This integrated approach is essential for uncovering the genetic basis of rare diseases and connecting findings to patient care.

Translational Research: From Bench to Bedside

Solve-RD is not just about discovering new genetic mutations; it’s about translating these findings into meaningful outcomes for patients. The initiative focuses on:

  • Validating genetic findings through functional studies to understand their role in disease mechanisms.
  • Improving diagnostic pipelines so that future patients can benefit from faster and more accurate diagnoses.
  • Laying the groundwork for personalized therapies tailored to the unique genetic profile of each patient.

Achievements and Future Vision

Solve-RD has already made significant progress in its mission. By systematically reanalyzing unsolved cases using new datasets and methodologies, the initiative has:

  • Increased diagnostic rates for rare diseases that previously defied explanation.
  • Identified novel genetic causes and mechanisms, expanding the understanding of rare conditions.
  • Helped characterize new syndromes, providing clarity for affected families and clinicians.

The long-term vision of Solve-RD is to create a sustainable diagnostic framework that can deliver accurate diagnoses for rare disease patients across Europe and beyond. By fostering collaboration, embracing innovation, and prioritizing patient-centered outcomes, Solve-RD is laying the foundation for the next generation of rare disease research and care.

Conclusion

Solve-RD is more than a research project—it is a beacon of hope for patients and families affected by rare diseases. Through its collaborative approach, cutting-edge technologies, and commitment to open data sharing, the initiative is addressing some of the most challenging medical mysteries of our time. As Solve-RD continues its work, it is transforming rare disease research and bringing answers to those who have waited far too long.

To get in touch with Solve-RD or learn more about the initiative, you can visit their official website:

Solve-RD Website: https://solve-rd.eu
RDMM Committees Contact: https://solve-rd.eu/rdmm-europe/rdmm-committees/
Olaf Riess University of Tübingen, Tübingen, Germany https://www.medizin.uni-tuebingen.de/de/das-klinikum/einrichtungen/institute/medizinische-genetik-und-angewandte-genomik

Paper: 

Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses
https://www.nature.com/articles/s41591-024-03420-w#Sec2

Efficient reinterpretation of rare disease cases using Exomiser https://www.nature.com/articles/s41525-024-00456-2?fromPaywallRec=false

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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