A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

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  • dc.contributor.author Denommé-Pichon, Anne-Sophie
  • dc.contributor.author Matalonga, Leslie
  • dc.contributor.author Faivre, Laurence
  • dc.date.accessioned 2023-06-19T06:05:36Z
  • dc.date.available 2023-06-19T06:05:36Z
  • dc.date.issued 2023
  • dc.description.abstract Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We 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). Conclusion: 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.
  • dc.description.sponsorship The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Denommé-Pichon AS, Matalonga L, de Boer E, Jackson A, Benetti E, Banka S, et al. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing. Genet Med. 2023 Apr;25(4):100018. DOI: 10.1016/j.gim.2023.100018
  • dc.identifier.doi http://dx.doi.org/10.1016/j.gim.2023.100018
  • dc.identifier.issn 1098-3600
  • dc.identifier.uri http://hdl.handle.net/10230/57220
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Genet Med. 2023 Apr;25(4):100018
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/779257
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/779257
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825575
  • dc.rights © 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword ClinVar
  • dc.subject.keyword Developmental disorder
  • dc.subject.keyword Exome reanalysis
  • dc.subject.keyword Rare diseases
  • dc.title A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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