New publication: reanalysis of 1,522 index cases from ERN-ITHACA

New publication: reanalysis of 1,522 index cases from ERN-ITHACA

Anne-Sophie Denommé-Pichon from CHU Dijon and colleagues from Solve-RD & ERN-ITHACA published "A Solve-RD ClinVar-based reanalysis of 1,522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing." in Genetics in Medicine.

Within the Solve-RD project, the ERN-ITHACA aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. In their recent paper they present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses and lessons learned.

Data from the first 3,576 exomes (1,522 probands and 2,054 relatives) collected from ERN-ITHACA was reanalyzed by the Solve-RD consortium by evaluating for the presence of SNV/indel already reported as (likely) pathogenic in ClinVar. Variants were filtered on frequency, genotype and mode of inheritance and reinterpreted.

They identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance or high frequency).

Anne-Sophei and colleagues conclude that the “ClinVar low-hanging fruit” analysis represents an effective, fast and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.

First RDMM Seeding Grant project received follow-up funding

First Seeding Grant project received follow-up funding

Solve-RD Seeding Grant recipient Alessandro Sessa successfully obtained a competitive grant from the Telethon/CARIPLO alliance in Italy.

Alessandro Sessa and his group at the IRCCS Ospedale San Raffaele, Milano, Italy have received Seeding Grant funding in April 2021 to validate rare missense variants identified by Siddharth Banka at the Manchester Centre for Genomic Medicine, UK. Based on preliminary data generated with the Solve-RD funding Alessandro Sessa successfully applied for a competitive grant from the Telethon/CARIPLO alliance (Italy) to continue the analysis (250.000€/2 years). The call (the first of its kind) was in support of basic research projects focusing on the study of genes/gene families, proteins, and RNA molecules whose function is unknown in rare diseases of genetic and non-genetic origin.

Holm Graessner receives the EURORDIS European Rare Disease Leadership Award 2023

Holm Graessner receives the EURORDIS European Rare Disease Leadership Award 2023

Holm Graessner receives the EURORDIS European Rare Disease Leadership Award 2023!

This is really a great honour, not just for me but for my team and the people I collaborate with. The dominating feeling is appreciation and gratefulness to the people I am privileged to work with in the area of rare diseases. And there are many nice and fit persons I collaborate with.

This is how Holm Graessner describes his surprise and joy about the award.

Since 2012, EURORDIS-Rare Diseases Europe has organized the Black Pearl Awards. Goal of the event is to recognise the major achievements and outstanding commitment of patient advocates, patient organisations, policymakers, scientists, companies, and media who strive to make a difference for the rare disease community.

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Solve-RD Treatabolome Webinar on YouTube

Solve-RD Treatabolome Webinar on YouTube

Solve RD Treatabolome webinar  given by Leslie Matalonga (CNAG-CRG) on 18 November 2022 is now available online!

The Treatabolome DB provides information on gene and variant-specific treatments for rare diseases. Currently, it includes up to 180 treatments associated with more than 1000 distinct variants - mainly for neuromuscular disorders.

In this webinar,we

  • provided an overview on the Treatabolome DB,
  • explained how to use the information,
  • showed how to find a treatment for a specific genetic disease and
  • showed how new data is being included and how you can contribute.

First RDMM-Europe project published

First RDMM-Europe project published

Solve-RD partners Ana Töpf and Volker Straub (John Walton Muscular Dystrophy Research Centre), together with Conrad Weihl and collaborators (Department of Neurology, Washington University School) have published their joint project in Acta Neuropathologica: "Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure". Conrad Weihl was one of the first scientists that received Seeding Grant funding from Solve-RD within the European Rare Disease Models & Mechanisms Network (RDMM-Europe) to validate a novel disease-causing gene identified by Ana Töpf and Volker Straub.

Weihl, C.C., Töpf, A., Bengoechea, R. et al. Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure. Acta Neuropathol (2022). https://doi.org/10.1007/s00401-022-02510-8.

Solve-RD Webinar: The Treatabolome DB

Solve-RD Webinar: The Treatabolome DB

In the last two years, the Treatabolome project, a Solve-RD initiative, promoted the collection of evidence about gene and variant-specific treatments for rare diseases. The information, gathered by experts and published in systematic literature reviews, is now stored and accessible in the Treatabolome DB. Currently, the database includes up to 180 treatments associated with more than 1000 distinct variants - mainly for neuromuscular disorders. Records are completed with clinical information by using standard vocabularies such as HPO, Orphanet, OMIM, Mesh and Chebi. The project is open to new data submissions and collaborations.

This webinar is especially relevant for people involved in rare disease diagnostics & care (clinicians, geneticists, genetic counsellors, etc). We will:

  • provide an overview on the Treatabolome DB
  • explain how to use the information
  • show how to find a treatment for a specific genetic disease
  • show how new data is being included and how you can contribute
Date: Friday, 18 November 2022, 2pm CET
Speakers: Sergi Beltran, Alberto Corvo, Leslie Matalonga (all CNAG-CRG)

Periodic report RP3

Periodic report RP3

The Solve-RD periodic report for the third reporting period has just been submitted.

In the last 18 months (from 01/2021 to 06/2022), we continued to implement the activities addressing the three challenges (see here).

We reached our goal and collected 21,348 datasets (phenotypic & exome/genome sequencing data) from unsolved RD patients and their family members. Standardised phenotypic information (HPO, ORDO & OMIM encoded) has been collected via the RD-Connect GPAP PhenoStore module.

We have continued producing and enriching the Rare Disease Case Ontology (RDCO). Up to now, RDCO has been populated with 412,500 similarity associations.

Re-analysis of data freezes 1 & 2 has been done by the Data Analysis Task Force DATF working groups. Results have been prioritized and interpreted by the Data Interpretation Task Forces (DITFs) of each ERN. This collaborative effort led to the diagnosis of 511 patients from 6,003 families. This is already an 8.5 % additional diagnostic rate although many of the analyses and evaluations are still ongoing. The new re-analysis approach pursued in Solve-RD as well as the structures we established to warrant best exchange of expertise have been published in a series of papers in the EJHG in June 2021.

Service providers have been chosen for all novel omics technologies. SOPs for biomaterials have been shared with all ERN partners via the DITFs. Sample shipment is only slowly progressing; however, >3,000 samples have been sent to the central lab in Nijmegen for QC and then further distributed to the respective service providers.

The RDMM-Europe brokerage service connecting Solve-RD partners who discovered novel RD genes with model organism scientists that have the expertise to functionally validate these genes and variants opened 10 calls for Connection Applications. 36 Seeding Grants have been awarded so far.

The co-designed models for the communication of genomic results for RD have been published (Costa et al.). The main finding at both study sites in the Czech Republic and the UK was the identification of post-test care as the shared priority for improvement for both health professionals and families.

The conference ECOgenomics “European Conference on the Diffusion of Genomic Medicine: Health Economics & Policy” took place online from 26-28 May 2021. Plenary sessions and parallel thematic sessions brought together researchers from the human sciences (mainly health economics), but also researchers from other disciplines.

The Treatabolome database has been released and an API connects it to the RD-Connect GPAP to make information about treatable genes and variants of RDs accessible and to improve the visibility of existing variant-specific treatment options at the time of diagnosis to clinicians and their patients. It includes data from 10 systematic literature reviews of which six have been published in a special issue in May 2021 in the JND.

The data flow system has continuously been adapted to the project’s needs involving GPAP, the EGA, omics service providers, the sandbox and RD3. GPAP’s new Cohort App module facilitates the exploration and construction of cohorts on experiments metadata and structured clinical data using standard ontologies to improve the analysis of defined cohorts. The FUSE client enables access to files stored at the EGA via the Sandbox and also for real-time visualisation in a genome browser like IGV when analysing data in the GPAP.

MSCA Action

MSCA-PF 2022 in peripheral nerve and muscle disease at University of Antwerp, Belgium

The Peripheral Neuropathy and Translational Neurosciences groups of the µNEURO Research Centre of Excellence (University of Antwerp, Belgium) welcome expressions of interest from postdoctoral researchers with a strong scientific track record to jointly prepare a high-quality proposal for an MSCA Postdoctoral Fellowship 2022 in the field of neuromuscular disease and peripheral nerve degeneration.

More info can be found here.

Solve-RD Annual Meeting 2022

Solve-RD Annual Meeting 2022

The Solve-RD Annual Meeting took place from Monday to Tuesday, 25-26 April 2022. Although virtually, it was a success!
It was great to see the results coming out of the project and to listen to all the fantastic presentations – especially from so many junior scientists. Congratulations to Robin Wijngaard (Nijmegen) and Vicente Yépez (Munich) for the best full presentation as well as Elke de Boer (Nijmegen) for the best flash talk!
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