Author: Birte Zurek

New Podcast Episode: Unsolved Cases? Genetic Re-Analysis! How Solve-RD Finds the Causes of Rare Diseases

New Podcast Episode: Unsolved Cases? Genetic Re-Analysis! How Solve-RD Finds the Causes of Rare Diseases

Solve-RD is featured in the latest episode of "Der Code des Lebens" by GHGA. In this episode, Dr. Holm Graessner and Prof. Dr. Alexander Hoischen discuss the challenges involved in diagnosing rare diseases, the role of Solve-RD’s genetic re-analysis approach in identifying previously undiagnosed conditions and the importance of international collaboration in addressing these complex cases.

Please note: The podcast is in German.

Listen to the full episode: https://codedeslebens.podigee.io/37-genetische-re-analyse

"Der Code des Lebens" is a podcast covering various topics in genome research. A new episode is released on the first Tuesday of each month. The podcast is aimed at anyone with an interest in science.

GHGA, the German Human Genome-Phenome Archive, provides a secure infrastructure for storing and accessing human genome data for biomedical research. The consortium includes 21 institutions across Germany and is funded by the German Research Foundation (DFG) as part of the National Research Data Infrastructure (NFDI).

 

New Solve-RD Publication in Nature Medicine

New Solve-RD Publication in Nature Medicine

New publication in Nature Medicine out now: Over 500 patients receive diagnosis through genetic reanalysis by Solve-RD!

It’s a great pleasure to share that our Solve-RD “flagship paper” was just published in Nature Medicine and is available online since Friday, 17th January 2025 at 11am CET.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.

Steven Laurie, Wouter Steyaert, Elke de Boer, Kiran Polavarapu, Nika Schuermans, Anna K. Sommer, […], Katja Lohmann, Richarda M. de Voer, Ana Töpf, Lisenka E.L.M. Vissers, Sergi Beltran, Alexander Hoischen. Genomic Reanalysis of a Pan-European Rare Disease Resource Yields New Diagnoses. doi: 10.1038/s41591-024-03420-w.

This research was conducted by the Solve-RD consortium and within four different ERNs, namely DITF-GENTURIS, DITF-ITHACA, DITF-EURO-NMD, and DITF-RND.

Press releases

Solve-RD paper on our interconnected data infrastructure is out!

Solve-RD paper on our interconnected data infrastructure is out!

Over the past five years, an ambitious collaboration has unfolded across 51 research institutes in 15 European countries. This effort, part of the Solve-RD project (HORIZON 2020 grant number 779257) and led by the University of Tübingen, aimed to unlock genetic diagnoses for patients with rare diseases who had reached the end of their diagnostic journey without answers.

At the heart of this project lies an extraordinary achievement: over 818 terabytes of data from more than 19,000 experiments were produced and reanalyzed, and securely stored at the EMBL-EBI European Genome-Phenome Archive (EGA). The data, contributed by six European Reference Networks, were combined with thousands of additional novel omics datasets, all processed and analyzed using cutting-edge and customized methods.

The backbone of this ambitious project was an interconnected data infrastructure that bridged existing components seamlessly. Participating centers submitted their data to the RD-Connect Genome-Phenome Analysis Platform (GPAP), hosted by the Centro Nacional de Análisis Genómico (CNAG) in Barcelona, where the data could also undergo advanced analysis. A high-performance computing cluster, or Sandbox, at the University Medical Center Groningen (UMCG) provided a testing ground for data analysts to explore and apply novel, best-in-class tools.

To ensure comprehensive tracking and discovery, cases were managed using the MOLGENIS RD3 database and Café Variome Discovery Nexus, developed by the UMCG and the University of Leicester, respectively. The integration of Beacon technology and a connection to Matchmaker Exchange further enhanced the discoverability of Solve-RD datasets, facilitating crucial patient matchmaking.

The innovative infrastructure and findings from this project are detailed in a recent paper published in GigaScience (https://doi.org/10.1093/gigascience/giae058) , showcasing the power of collaboration in pushing the boundaries of rare disease research:

Lennart F. Johansson, Steve Laurie, Dylan Spalding, [...] Sergi Beltran, Morris A. Swertz, Anthony J. Brookes, and Solve-RD consortium. An interconnected data infrastructure to support large-scale rare disease research. Gigascience. 2024 Jan 2:13:giae058. doi: 10.1093/gigascience/giae058.

Solve-RD industry workshop: Strategies for omics data analysis & reanalysis – recording available

Solve-RD industry workshop: Strategies for omics data analysis & reanalysis - recording available

On Thursday, 20 June 2024, Solve-RD organized a webinar “Solve-RD industry workshop: Strategies for omics data analysis & reanalysis”. The aim was to present participants from industry the strategies we developed for Solve-RD for omics data analysis and reanalysis, and to discuss challenges, advantages as well as future developments.

The recording has been uploaded to our Solve-RD YouTube channel and is available via this link.

New Publication: Model matchmaking via the Solve-RD Rare Disease Models & Mechanisms Network (RDMM-Europe)

New Publication: Model matchmaking via the Solve-RD Rare Disease Models & Mechanisms Network (RDMM-Europe)

The European Rare Disease Models & Mechanisms Network (RDMM-Europe) has been established within Solve-RD. RDMM-Europe is a brokerage service to promote fruitful collaborations between clinicians and model organism experts with the aim of filling the gap between RD gene discovery and functional validation of potentially new disease genes and/or novel disease mechanisms.

In our article we describe the network and infrastructure that we have successfully implemented to support the use of model organisms in rare disease research, we share our processes and highlight several examples of modeling approaches that clearly illustrate the benefit and need of functional validation in model organisms to accelerate the assessment of new disease-gene associations. The article also showcases the main objectives of the funded projects, highlights examples of validation projects in different models and provides links to recent publications related to some of these projects.

The article has now been accepted for publication in Lab Animal: Kornelia Ellwanger, Julie A. Brill [...] Olaf Riess. Model matchmaking via the Solve-RD Rare Disease Models & Mechanisms Network (RDMM-Europe). Lab Anim (NY). 2024 Jun 24. https://doi.org/10.1038/s41684-024-01395-2. Epub ahead of print.

Solve-RD industry workshop

Solve-RD industry workshop: Strategies for omics data analysis & reanalysis

Date: Thursday, 20 June 2024, 12:00-13:30 CEST | online

Aim: The strategies we developed for Solve-RD for omics data analysis and reanalysis will be presented. We will discuss challenges, advantages as well as future developments.

Participants: Representatives from industry

Agenda:

  1. Welcome
  2. Data reanalysis approach - Sergi Beltran (CNAG, Barcelona, Spain)
  3. Solvathon concept - Holm Graessner (Uni Tübingen, Germany)

    • Example from RNAseq & multi-omics Solvathon - Vicente Yepez (TU Munich, Germany) & Anna Esteve (CNAG, Barcelona, Spain)
    • Example from long-read sequencing &  Optical Genome Mapping Solvathon - Alexander Hoischen (RadboudUMC, Nijmegen, the Netherlands)
  4. Q & A
  5. Perspective - Holm Graessner (Uni Tübingen, Germany)

RDMM-Europe project published!

RDMM-Europe project published!

Solve-RD partner Laurence Faivre from CHU Dijon and colleagues from CHU Rouen, France identified 5 patients with a recurrent de novo variant p.(Arg126Gln) in FEM1B and a neurodevelopmental disorder associated with a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities.

The RDMM-Europe Seeding Grant awarded to Ype Elgersma at Erasmus University Medical Center in Rotterdam helped to assess the pathogenicity of this rare genetic variant. The project involved expression of the mutant form in developing mouse embryos and in primary neuronal cultures and demonstrated the toxicity of FEM1BR126Q variant compared to FEM1B.

The collaborative work was now accepted for publication in Genetics in Medicine:

François Lecoquierre, […] Laurence Faivre, Ype Elgersma, Antonio Vitobello. A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder. Genetics in Medicine, Volume 26, Issue 6, 2024, 101119, ISSN 1098-3600, https://doi.org/10.1016/j.gim.2024.101119