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A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
AS. Denommé-Pichon, L. Matalonga, E. de Boer, A. Jackson, E. Benetti, S. Banka, AL. Bruel, A. Ciolfi, J. Clayton-Smith, B. Dallapiccola, Y. Duffourd, K. Ellwanger, C. Fallerini, C. Gilissen, H. Graessner, TB. Haack, M. Havlovicova, A. Hoischen,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc23010573
- MeSH
- alely MeSH
- genotyp MeSH
- lidé MeSH
- mentální retardace * diagnóza genetika MeSH
- sekvenování exomu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Centre for Rare Diseases University Hospital Tübingen Tübingen Germany
Department of Genetics Assistance Publique Hôpitaux de Paris Université de Paris Paris France
Department of Human Genetics Radboudumc Nijmegen The Netherlands
Donders Institute for Brain Cognition and Behaviour Radboudumc Nijmegen The Netherlands
INSERM UMR 1141 NeuroDiderot Hôpital Robert Debré Paris France
Institute of Medical Genetics and Applied Genomics University of Tübingen Tübingen Germany
Manchester Centre for Genomic Medicine University of Manchester Manchester United Kingdom
Medical Genetics Azienda Ospedaliero Universitaria Senese Siena Italy
Medical Genetics University of Siena Siena Italy
Molecular Genetics and Functional Genomics Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy
Radboud Institute for Molecular Life Sciences Radbound University Nijmegen The Netherlands
Citace poskytuje Crossref.org
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- $a A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing / $c AS. Denommé-Pichon, L. Matalonga, E. de Boer, A. Jackson, E. Benetti, S. Banka, AL. Bruel, A. Ciolfi, J. Clayton-Smith, B. Dallapiccola, Y. Duffourd, K. Ellwanger, C. Fallerini, C. Gilissen, H. Graessner, TB. Haack, M. Havlovicova, A. Hoischen, N. Jean-Marçais, T. Kleefstra, E. López-Martín, M. Macek, MA. Mencarelli, S. Moutton, R. Pfundt, S. Pizzi, M. Posada, FC. Radio, A. Renieri, C. Rooryck, L. Ryba, H. Safraou, M. Schwarz, M. Tartaglia, C. Thauvin-Robinet, J. Thevenon, F. Tran Mau-Them, A. Trimouille, P. Votypka, BBA. de Vries, MH. Willemsen, B. Zurek, A. Verloes, C. Philippe, Solve-RD DITF-ITHACA, Solve-RD SNV-indel Working Group, Solve-RD Consortia, Orphanomix Group, A. Vitobello, LELM. Vissers, L. Faivre
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- 700 1_
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