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A Solve-RD ClinVar-based reanalysis of 1,522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

  • Anne-Sophie Denommé-Pichon
    Correspondence
    Corresponding authors: Dr Anne-Sophie Denommé-Pichon, MD, Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, 15 boulevard Maréchal de Lattre de Tassigny, 21070 Dijon, France, Phone: +33 (0)3 80 39 32 38 / Fax: +33 (0)3 80 29 32 66,
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Leslie Matalonga
    Affiliations
    CNAG CRG, Centre for Genomic Regulation”, The Barcelona Institute of Science and Technology, Barcelona, Spain
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  • Elke de Boer
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
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  • Adam Jackson
    Affiliations
    Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK
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  • Elisa Benetti
    Affiliations
    Med Biotech Hub and Competence Center, Dept of Medical Biotechnologies, University of Siena, Italy
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  • Siddharth Banka
    Affiliations
    Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK
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  • Ange-Line Bruel
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Andrea Ciolfi
    Affiliations
    Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
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  • Jill Clayton-Smith
    Affiliations
    Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK
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  • Bruno Dallapiccola
    Affiliations
    Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
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  • Yannis Duffourd
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Kornelia Ellwanger
    Affiliations
    Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
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  • Chiara Fallerini
    Affiliations
    Med Biotech Hub and Competence Center, Dept of Medical Biotechnologies, University of Siena, Italy

    Medical Genetics, University of Siena, Siena, Italy
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  • Christian Gilissen
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
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  • Holm Graessner
    Affiliations
    Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
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  • Tobias B. Haack
    Affiliations
    Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
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  • Marketa Havlovicova
    Affiliations
    Dept of Biology and Medical Genetics, Charles University Prague, Prague, Czech Republic
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  • Alexander Hoischen
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands

    Dept of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboudumc, Nijmegen, the Netherlands
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  • Nolwenn Jean-Marçais
    Affiliations
    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France

    Dept of Genetics and Reference Center for Development disorders and intellectual disabilities, FHU TRANSLAD and GIMI Institute, CHU Dijon Bourgogne, Dijon, France
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  • Tjitske Kleefstra
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands

    Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands
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  • Estrella López-Martín
    Affiliations
    Institute of Rare Diseases Research, Spanish Undiagnosed Rare Diseases Cases Program (SpainUDP) & Undiagnosed Diseases Network International (UDNI), Instituto de Salud Carlos III, Madrid, Spain
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  • Milan Macek Jr.
    Affiliations
    Dept of Biology and Medical Genetics, Charles University Prague, Prague, Czech Republic
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  • Maria Antonietta Mencarelli
    Affiliations
    Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
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  • Sébastien Moutton
    Affiliations
    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Rolph Pfundt
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
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  • Simone Pizzi
    Affiliations
    Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
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  • Manuel Posada
    Affiliations
    Institute of Rare Diseases Research, Spanish Undiagnosed Rare Diseases Cases Program (SpainUDP) & Undiagnosed Diseases Network International (UDNI), Instituto de Salud Carlos III, Madrid, Spain
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  • Francesca Clementina Radio
    Affiliations
    Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
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  • Alessandra Renieri
    Affiliations
    Med Biotech Hub and Competence Center, Dept of Medical Biotechnologies, University of Siena, Italy

    Medical Genetics, University of Siena, Siena, Italy

    Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
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  • Caroline Rooryck
    Affiliations
    University Bordeaux, MRGM INSERM U1211, CHU de Bordeaux, Service de Génétique Médicale, Bordeaux, France
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  • Lukas Ryba
    Affiliations
    Dept of Biology and Medical Genetics, Charles University Prague, Prague, Czech Republic
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  • Hana Safraou
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Martin Schwarz
    Affiliations
    Dept of Biology and Medical Genetics, Charles University Prague, Prague, Czech Republic
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  • Marco Tartaglia
    Affiliations
    Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
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  • Christel Thauvin-Robinet
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France

    Dept of Genetics and Reference Center for Development disorders and intellectual disabilities, FHU TRANSLAD and GIMI Institute, CHU Dijon Bourgogne, Dijon, France
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  • Julien Thevenon
    Affiliations
    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Frédéric Tran Mau-Them
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Aurélien Trimouille
    Affiliations
    Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, CHU Bordeaux – Hôpital Pellegrin, Bordeaux, France
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  • Pavel Votypka
    Affiliations
    Dept of Biology and Medical Genetics, Charles University Prague, Prague, Czech Republic
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  • Bert B.A. de Vries
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
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  • Marjolein H. Willemsen
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
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  • Birte Zurek
    Affiliations
    Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
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  • Alain Verloes
    Affiliations
    Dept of Genetics, Assistance Publique-Hôpitaux de Paris - Université de Paris, Paris, France

    INSERM UMR 1141 “NeuroDiderot”, Hôpital Robert Debré, Paris, France
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  • Christophe Philippe
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Solve-RD DITF-ITHACA
  • Solve-RD SNV-indel working group
  • Solve-RD Consortia
  • Orphanomix Group
  • Antonio Vitobello
    Affiliations
    Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France
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  • Lisenka E.L.M. Vissers
    Affiliations
    Dept of Human Genetics, Radboudumc, Nijmegen, The Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
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  • Laurence Faivre
    Correspondence
    Pr. Laurence Faivre, MD-PhD, FHU-TRANSLAD, Centre de Génétique, Hôpital d’Enfants, CHU Dijon Bourgogne, 14 rue Paul Gaffarel, 21073 Dijon, France, Phone: +33 (0)3 80 29 53 13 / Fax: +33 (0)3 80 29 32 66,
    Affiliations
    UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement”, FHU-TRANSLAD, Dijon, France

    Dept of Genetics and Reference Center for Development disorders and intellectual disabilities, FHU TRANSLAD and GIMI Institute, CHU Dijon Bourgogne, Dijon, France
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Open AccessPublished:January 19, 2023DOI:https://doi.org/10.1016/j.gim.2023.100018
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      Abstract

      Purpose

      Within the Solve-RD project (https://solve-rd.eu/), the ERN-ITHACA (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 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.

      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.

      Keywords