Author: Birte Zurek

The ‘Mouse Genetics and Genomic Medicine’ virtual conference organised from 23-24 September 2021 by the International Mouse Phenotyping Consortium –IMPC (https://www.mousephenotype.org) will celebrate the occasion of the 10th anniversary of the establishment of the IMPC.

Solve-RD will present a poster on "Model Matchmaking via the Rare Diseases Models & Mechanisms Network (RDMM-Europe)".

In medical genetics, there is a critical need for model organism research, to assess new disease-gene associations, to understand pathophysiology and to test potential therapies. Within the Solve-RD project we established the European Rare Disease Models & Mechanisms Network (RDMM-Europe) to facilitate fruitful collaborations of model organism researchers and clinicians following patients with rare diseases (RD). The principle of this brokerage service is to fill the gap between RD gene discovery and functional validation. For that purpose, we connect Solve-RD clinicians that have discovered new disease-causing genes with model organism investigators (MOIs) that can study the mechanistic role of the given genes in health and disease by using an appropriate model organism or cell culture system. Solve-RD supports these validation projects with 50 Seeding Grants of 20,000 EUR each.

For the selection of candidate genes and model matchmaking, a two-committee process and a registry were set up using the structures of the successful Canadian RDMM Network as role model. The RDMM-Europe registry is a database that allows all interested MOIs to register the genes and model organisms they work with. Registrants express interest in getting linked to clinicians representing patients with RD and collaborating in projects funded by Solve-RD. The RDMM-Europe registry is also linked to international partner networks. Connection Applications on novel RD candidate genes are submitted by Solve-RD clinicians and are evaluated and approved by the Clinical Advisory Committee. Upon approval, the project management office opens a call for tender to identify best matching MOIs for the requested validation work and invites them to submit Seeding Grant Applications. They are evaluated by a Scientific Advisory Committee and approved for funding.

To date, we have awarded 23 Seeding Grants to MOIs and have linked Solve-RD scientists to model researchers in eight European countries, Canada, USA, Qatar and Australia. Linking scientists across borders via the RDMM network and supporting these joint projects will advance RD research and will benefit patients and families living with RD.

View the poster here.

Núria Dueñas, a medical oncologist and PhD candidate at the Catalan Institute of Oncology (ICO/IDIBELL) in Barcelona, spent 6 weeks at the Institute of Human Genetics of the University Hospital Bonn, Germany to conduct research with Solve-RD partner Stefan Aretz. They investigated whether different hereditary colorectal cancer risks can be in part attributable to the accumulation of low-risk SNPs in patients with Lynch syndrome. Her stay was supported by the EJP RD fellowship program.

Núria Dueñas is a medical oncologist with a special interest in cancer genetics and hereditary cancer. Since 2018, she works as a physician in the Hereditary Cancer Program of the Catalan Institute of Oncology (ICO/IDIBELL) in Barcelona and as a PhD student co-supervised by Marta Pineda and Joan Brunet. In the past years, she focussed on hereditary colorectal cancer (CRC) and Lynch syndrome (LS). Her PhD project is on risk estimation and phenotype-genotype correlation in LS.

In LS, as in other hereditary cancer predisposition syndromes characterized by incomplete penetrance, one of the main challenges is to identify which risk-modifying factors may be modulating the expression of the oncological disease. Common low-risk alleles (SNPs) for CRC can be integrated in Polygenic Risk Scores (PRS) which have been shown to model CRC risk in the general population as one type of genetic risk modifiers, but to date their effect on CRC risk in LS individuals is still largely unknown.

Núria spent 6 weeks at the Institute of Human Genetics of the University Hospital Bonn, Germany in the group of Stefan Aretz. They investigated whether different CRC risks can be in part attributable to the accumulation of low-risk SNPs in LS individuals. In particular, Núria gathered and aggregated clinical data of the LS cohort in Bonn (n=500) and supported the biostatistics team in Bonn to apply the Barcelona PRS pipeline. This collaborative project continues now that she is back in Barcelona through the application of additional models to calculate the PRS. Also, a meta-analysis combining the two populations included (Bonn and Barcelona) will be conducted. The collaborative study will hopefully lead to a first publication of the findings; follow-up projects are already planned.

The EJP-RD mobility fellowship has been a unique opportunity for Núria. She said: “Collaborating with professionals from different specialties and different countries has helped, not only to generate new knowledge in translational research and in the development of research projects but also to learn different ways of approaching scientific research”. Moreover, she has had the chance to refresh her German speaking skills – at least to order food and drinks by herself. And she was able to enjoy the rainiest summer of her life!

Solve-RD will host two webinars on features of the RD-Connect Genome-Phenome Analysis Platform (GPAP) in October 2021. The first webinar focuses on basic analyses and the second webinar focuses on advanced platform features. Everyone who is interested is invited to register and join the webinars. Both webinars have also been recognised by the Spanish Society of Human Genetics (AEGH).

Webinar 1: RD-Connect GPAP webinar - general analysis

Time: Wednesday, 6 October 2021; 2-3 pm CEST

Speaker: Steven Laurie (CNAG, Barcelona)

Audience: Solve-RD partners that have no (or very few) previous experience analysing (filtering and prioritising) genomic data through the GPAP. Users will learn how to filter and prioritise variants (SNVs, InDels, and CNVs) using common annotations and on-the-fly gene panels associated to diseases, phenotypes, and pathways (OMIM, ORDO, HPO, PanelApp, Reactome), how to interpret genomic variants according to ACMG guidelines and how to use integrated tools such as Exomiser, Mendelian.co, ClinVar, and Varsome.

Registration link: https://us02web.zoom.us/webinar/register/WN_I7j_J3ZMSOOBBZHI7rhTBg

 

Webinar 2: RD-Connect GPAP webinar- advanced platform features

Time: Tuesday, 19 October 2021; 2-3 pm CEST

Speaker: Leslie Matalonga (CNAG, Barcelona)

Audience: Solve-RD partners that already have previous experience analysing (filtering and prioritising) genomic data through the GPAP and/or have attended the workshop on basic analysis. Users will learn how to use advanced features integrated in the system such as: i) Matchmaker exchange, ii) search for specific gene/variants across all samples, iii) TAG and share variants / queries, iv) create specific cohorts based on phenotypic data and v) post analysis management (analysis status and solved cases).

Registration Link: https://us02web.zoom.us/webinar/register/WN_VkSDSM50RDedwoc7Y4C2sA

Every person living with a rare disease is a reason for Europe to take action on rare diseases that leaves no one behind by 2030.

Solve-RD joined EURORDIS and the rare disease community in the #30millionreasons campaign for a new EU Action Plan on rare diseases, that will leave no one behind by 2030. We have #30millionreasons for Europe to take action to.

And here is ours: We need a European action plan on rare diseases…

… because we need a European strategy that allows all unsolved rare disease patients entering a transnational research and diagnostic pipeline.

More information can be found here.

A special issue dedicated to the “Treatabolome” has been published in the Journal of Neuromuscular Diseases.

The special issue covers systematic reviews of gene- and variant-specific treatments for rare diseases, particularly rare neurological and neuromuscular disorders, thereby highlighting the important premise that a precise genetic diagnosis may result in equally precise therapeutic approaches.

All articles can be found here.

For the first time in Europe hundreds of rare disease experts team up to actively share and jointly analyze existing data from unsolved rare disease patients. The Solve-RD project published a series of papers in the European Journal of Human Genetics describing the new approach and the structures established to warrant best exchange of expertise. Involved in the project are data scientists and genomics experts as well as expert clinicians and geneticists from the European Reference Networks (ERNs). In an accompanying paper the first results of the approach to solve rare diseases through programmatic reanalysis of genome-phenome data are described. In addition, four case reports from the ERNs show the advantage of the approach and provide details why the patients have only now received their diagnosis.

• Zurek et al. “Solve-RD: systematic Pan-European data sharing and collaborative analysis to solve Rare Diseases.”; doi: 10.1038/s41431-021-00859-0
• Matalonga et al. “Diagnosis of rare disease patients through programmatic reanalysis of genome-phenome data.”; doi: 10.1038/s41431-021-00852-7
• de Boer et al. “A pathogenic MT-TL1 variant identified by whole exome sequencing in an individual with unexplained intellectual disability, epilepsy and spastic tetraparesis.”; doi: 10.1038/s41431-021-00900-2
• Töpf et al. “Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1).”; doi: 10.1038/s41431-021-00851-8
• te Paske et al. “A Mosaic PIK3CA Variant in a Young Adult with Diffuse Gastric Cancer: Case Report.”; doi: 10.1038/s41431-021-00853-6
• Schüle et al. “Solving unsolved rare neurological diseases—a Solve-RD viewpoint.”; doi: 10.1038/s41431-021-00901-1

A press release has been published by the University Hospital Tübingen in German and in English.
And here is the link to the press release from the Radboud UMC in Dutch.

The editorial accompanying our six paper bundle:
Graessner H, Zurek B, Hoischen A et al. Solving the unsolved rare diseases in Europe. Eur J Hum Genet (2021). https://doi.org/10.1038/s41431-021-00924-8; Link to the editorial.