Tag: reanalysis

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

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-Sophie 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.