New form of research facilitates diagnoses of rare diseases

A family member of a patient said it was “a relief” that his son finally was diagnosed after 20 years of no answers. 

"We now have clarity, I did not expect that we would ever get an answer," the parent of one of the participants said in a statement keeping animosity. 

Receiving a diagnosis often marks the end of a long journey, in most cases lasting over five years, known as the diagnostic odyssey. 

A program founded to diagnose life-limiting diseases has diagnosed over 500 patients from 12,000 different families. The Solving the Unsolved Diseases agency (Solve-RD), founded in 2018 by the European Union, is the program that conducted the recent diagnoses on rare diseases patients. 

All patients under treatment suffered from a wide variety of rare diseases, including rare neurological disorders, malformation syndromes and severe intellectual disabilities, rare neuromuscular diseases, and hereditary cancers. 

Prior to the program, all patients had gone through exome or genome sequencing analysis, but none of them were given a diagnosis. 

Genome sequencing is the study to identify genetic variants in the DNA that have an impact on health or diseases. Meanwhile, exome sequencing focuses on the protein-coding regions to find genetic mutations. 

Solve-RD diagnosed 500 patients based on a comprehensive reprocessing, systematic reanalysis and reinterpretation of data collected through the years.  

In the reported research, which involved the reanalysis of genetic information from more than 10,000 individuals, from over 6,000 families, the researchers discovered that 84% of cases could be attributed to small genetic alterations, involving the change of just a single DNA letter. 

From the 7,000 diseases known, the study concluded that at least 70% of the rare diseases were from a genetic origin, putting at risk future generations of the family.  

All the families involved in the program came from four of the 24 European Reference Networks (ERNs), virtual communities of healthcare providers focused on rare diseases and the Spanish Undiagnosed Disease Program.  

ERNs are cross-border networks that bring together European hospital centers of expertise to tackle rare and complex diseases.   

Participants in the research 

Solve-RD has had the contribution of 37 research centers, 12 European countries and Canada and was coordinated by the University of Tübingen in Germany. 

The data collection was conducted by Spain's National Center for Genomic Analysis (CNAG), an organization founded by the Spanish ministry and Catalan government, in partnership with Radboud University Medical Center (The Netherlands) and the University of Tübingen (Germany). 

The CNAG takes part in genome sequencing and analysis in areas such as cancer genetics and rare diseases.   

CNAG researchers Dr Steven Laurie and Dr Sergi Beltran, who contributed as authors of the study, cover the reanalysis of around half of the data collected by Solve-RD. 

Dr. Steven Laurie pointed out "Bringing together diverse analytical and clinical expertise from across Europe made a major difference. It allowed us to organize the project according to clinical hypotheses and to respond with specific analyses to the questions and needs raised by the clinical experts." 

Data showed that 1 in 2,000 people are affected at least once in their lifetime by a rare disease.  

What comes next? 

Despite providing many diagnoses, Solve-RD looks to keep increasing the number of diagnoses and work in improving research on rare diseases.  

The creation of the European Rare Diseases Research Alliance (ERDERA) is one of the first building blocks to improve diagnosis of rare diseases. This initiative, in which CNAG will also be involved, aims to scale up patient data reanalysis and cover a much wider range of rare genetic conditions. 

Dr. Sergi Beltran indicated that “ERDERA will also emphasize the translation of successful approaches to standard clinical diagnostic pathways." 

"These approaches might include the integration of innovative techniques such as long-read genome sequencing, optical genome mapping, and RNA sequencing. The use of these methods, which was piloted in the Solve-RD project, makes it possible to achieve more and faster diagnoses for unresolved rare conditions," he added. 

The ERDERA project is set to kick off in September of 2025 and looks to improve the analysis of data to help with diagnoses for families affected by rare diseases.