Rare Diseases (RD for short) occur very sporadically
It was important news in 2018. A consortium led by Tübingen University, Radboudumc and Leicester University had received 15 million European subsidy for the research program SOLVE-RD. This meant that the diagnosis of rare diseases had to be considerably improved. More than three years later, the consortium is fulfilling its first promises with the publication of no fewer than six articles in the European Journal of Human Genetics. Two of them (GENTURIS and ITHACA) bear the stamp of Radboudumc researchers.
Rare diseases (Rare Diseases, RD for short) occur only very sporadically. But add up all those rare diseases and they are actually very common. Then suddenly it concerns about 30 million people in Europe. It is estimated that more than 70 percent of all those rare diseases have a genetic cause. The Solve-RD project had to link all this scattered knowledge of rare diseases, use new techniques, cross-link existing data and re-analyze it. Within European countries, for example, the available expertise could be used much better and more patients with a rare disease could be diagnosed.
Extra step
Geneticists Alexander Hoischen and Han Brunner, involved in the project from Radboudumc from the very beginning, explain the need for this approach: “Getting a diagnosis can be a long and difficult process for a patient with a rare disease. Some patients take months, years, or even their entire lives to get a correct diagnosis. Let alone the right therapy. About fifty percent of patients with a rare disease do not receive a diagnosis, even after all of that patient’s genes have been mapped and analyzed. Apparently, even better genetic tests and interpretations are needed for an effective diagnosis of the rare diseases. Taking that extra step is the main goal of the Solve-RD project.”
Referentienetwerken
An important role in Solve-RD is reserved for the clinicians and geneticists of the previously established European Reference Networks (ERNs). These European reference networks for rare and complex diseases illustrate that European cooperation can be a real game changer in tackling rare diseases. Solve-RD is built on a core group of four European reference networks (ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) that see more than 270,000 patients with a rare disease every year. One of these ERNs, ERN-GENTURIS, is coordinated from Nijmegen by Nicoline Hoogerbrugge, and the other three by European cooperation partners.
Two approaches
Hoischen: “Solve-RD’s main ambition is to solve unresolved rare diseases whose molecular cause is not yet known. We do this through innovative clinical research in which we introduce new ways to organize the available expertise and data. Mainly two approaches are followed. On the one hand, a large-scale new analysis of already available data from more than 19,000 unresolved patients with rare diseases. On the other hand, we combine the data from various -omics approaches. Simply put: we combine data from DNA with RNA (genomics/transcriptomics), proteins (proteomics), metabolic products (metabolomics), and so on.”
DNA re-examined
The European Journal of Human Genetics now publishes six articles on the Solve-RD approach. These studies mainly focus on a large-scale re-analysis of the available data. The results of the -omics approach will also follow later.
In the publication by Elke de Boer, Lisenka Vissers and colleagues, which stems from ERN-ITHACA, a patient’s genetic information (the data from the exome sequencing) was reviewed and analyzed. Vissers: “Exome sequencing primarily looks at the DNA in the cell nucleus. But in the mitochondria, DNA is also present. Although exome sequencing is not specifically aimed at finding variants (‘mutations’) in mitochondrial DNA, those variants can be picked up.”
Mutation in the battery
Systematic analysis of mitochondrial DNA in a large research group can lead to surprising diagnoses, according to the study they describe. It is a description of a young man with a complex developmental disorder, caused by a variant in a gene (MT-TL1) in the mitochondrial DNA. Mitochondria are the batteries, the power plants in the cell. Vissers: “Due to the atypical clinical picture, a mitochondrial disorder was never thought of on clinical grounds. That is why the mitochondrial DNA has never been analysed. However, with the current knowledge of the variant in mitochondrial DNA, we see several features in the patient that fit into the broad picture of the condition caused by mutations in MT-TL1. And now we can make the diagnosis. Analysis of the mitochondrial DNA from the exome sequencing is therefore particularly relevant for patients with atypical features. And for their relatives and future children.”
Mosaic of cells
It article by Iris te Paske, Richarda de Voer and colleagues was generated from the European Reference Network for Rare Genetic Tumor Risk Syndromes (ERN-GENTURIS). A re-analysis of exome data from genetically unexplained hereditary gastric and colorectal cancer patients is central. In this reanalysis they encountered a 25-year-old patient with diffuse gastric cancer who was a carrier of a pathogenic variant of the gene PIK3CA. De Voer: “Changes in PIK3CA are often involved in the development of tumors and the variant has therefore been repeatedly found in cancer. It often also leads to ‘overgrowth’, where certain parts of the body grow too fast or have abnormal body characteristics. But these external features were not visible in the patient, so this gene was not thought of either.” The re-analysis also provided a certain explanation for this. The mutation in the gene was only present in some of the patient’s cells and not in all cells. This phenomenon is called mosaicism. De Voer: “If the variant only occurs in a small part of the patient’s germline DNA, the symptoms of the disease are usually less or less severe. Our case description thus shows that mosaic variants may be a new and underestimated mechanism in the development of diffuse gastric cancer.”
Solve RD works
Hoischen, who is also involved as an author in several publications, sees the articles as confirmation of the chosen approach: “The articles illustrate that Solve-RD provides extra diagnoses, which is extremely important for individual patients and families. From a societal perspective, Solve-RD proves one important point: collaborative European research is an ideal tool to mobilize and organize the interdisciplinary clinical and scientific resources required to address the diagnosis of rare diseases and influence the way care is delivered. is provided on a national and local scale.”
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