A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
journal contribution
posted on 2024-12-03, 15:36 authored by Anne-Sophie Denommé-Pichon, Leslie Matalonga, Elke de Boer, Adam Jackson, Elisa Benetti, Siddharth Banka, Ange-Line Bruel, Andrea Ciolfi, Jill Clayton-Smith, Bruno Dallapiccola, Yannis Duffourd, Kornelia Ellwanger, Chiara Fallerini, Christian Gilissen, Holm Graessner, Tobias B Haack, Marketa Havlovicova, Alexander Hoischen, Nolwenn Jean-Marçais, Tjitske Kleefstra, Estrella López-Martín, Milan Macek, Maria Antonietta Mencarelli, Sébastien Moutton, Rolph Pfundt, Simone Pizzi, Manuel Posada, Francesca Clementina Radio, Alessandra Renieri, Caroline Rooryck, Lukas Ryba, Hana Safraou, Martin Schwarz, Marco Tartaglia, Christel Thauvin-Robinet, Julien Thevenon, Frédéric Tran Mau-Them, Aurélien Trimouille, Pavel Votypka, Bert BA de Vries, Marjolein H Willemsen, Birte Zurek, Alain Verloes, Christophe Philippe, Kristin M Abbott, Laurence Faivre, Mieke Kerstjens, Estrella López Martín, Isabelle Maystadt, Manuela Morleo, Vicenzo Nigro, Michele Pinelli, Francesca C Radio, Olaf Riess, Jean-Madeleine de Sainte Agathe, Gijs WE Santen, Christel Thauvin, Annalaura Torella, Lisenka Vissers, Antonio Vitobello, Kristina Zguro, Enzo Cohen, Daniel Danis, Fei Gao, Rita Horvath, Mridul Johari, Lennart Johanson, Shuang Li, Heba Morsy, Isabelle Nelson, Ida Paramonov, Iris BAW te Paske, Peter Robinson, Marco Savarese, Wouter Steyaert, Ana Töpf, Joeri K van der Velde, Jana Vandrovcova, Stephan Ossowski, German Demidov, Marc Sturm, Julia M Schulze-Hentrich, Rebecca Schüle, Jishu Xu, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Holger Lerche, Josua Kegele, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Peter AC ‘t Hoen, Lisenka ELM Vissers, Karolis Sablauskas, Richarda M de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Marloes Steehouwer, Burcu Yaldiz, Anthony J Brookes, Colin Veal, Spencer GibsonSpencer Gibson, Vatsalya Maddi, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Volker Straub, Chiara Marini Bettolo, Jordi Diaz Manera, Sophie Hambleton, Karin Engelhardt, Elizabeth Alexander, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, David Lagorce, Oscar Hongnat, Maroua Chahdil, Emeline Lebreton, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Antonio Atalaia, Tanya Stojkovic, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Petra Lišková, Pavla Doležalová, Helen Parkinson, Thomas Keane, Mallory Freeberg, Coline Thomas, Dylan Spalding, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Stephanie Efthymiou, Elisa Cali, Francesca Magrinelli, Sanjay M Sisodiya, Jonathan Rohrer, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Geert de Vries, Jonathan De Winter, Danique Beijer, Peter de Jonghe, Liedewei Van de Vondel, Willem De Ridder, Sarah Weckhuysen, Vincenzo Nigro, Margherita Mutarelli, Alessandra Varavallo, Sandro Banfi, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Francesca Gualandi, Stefania Bigoni, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A Swertz, Lennart Johansson, Gerben van der Vries, Pieter B Neerincx, David Ruvolo, Wilhemina S Kerstjens Frederikse, Eveline Zonneveld-Huijssoon, Dieuwke Roelofs-Prins, Marielle van Gijn, Sebastian Köhler, Alison Metcalfe, Séverine Drunat, Delphine Heron, Cyril Mignot, Boris Keren, Didier Lacombe, Aurelien Trimouille, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Maria-Roberta Cilio, Evelina Carpancea, Chantal Depondt, Damien Lederer, Yves Sznajer, Sarah Duerinckx, Sandrine Mary, Alfons Macaya, Ana Cazurro-Gutiérrez, Belén Pérez-Dueñas, Francina Munell, Clara Franco Jarava, Laura Batlle Masó, Anna Marcé-Grau, Roger Colobran, Peter Hackman, Bjarne Udd, Dimitri Hemelsoet, Bart Dermaut, Nika Schuermans, Bruce Poppe, Hannah Verdin, Andrés Nascimento Osorio, Christel Depienne, Andreas Roos, Isabell Cordts, Marcus Deschauer, Pasquale Striano, Federico Zara, Antonella Riva, Michele Iacomino, Paolo Uva, Marcello Scala, Paolo Scudieri, Ayşe Nazlı Başak, Kristl Claeys, Kaan Boztug, Matthias Haimel, Gijs W.E, Claudia AL Ruivenkamp, Daniel Natera de Benito, Rachel Thompson, Kiran Polavarapu, Bodo Grimbacher, Ioannis Zaganas, Evgenia Kokosali, Mathioudakis Lambros, Athanasios Evangeliou, Martha Spilioti, Elisabeth Kapaki, Mara Bourbouli, Peter Balicza, Maria Judit Molnar, Manuel Posada De la Paz, Eva Bermejo Sánchez, Beatriz Martínez Delgado, F Javier Alonso García de la Rosa, Evelin Schröck, Andreas Rump, Davide Mei, Annalisa Vetro, Simona Balestrini, Renzo Guerrini, Patrick F Chinnery, Thiloka Ratnaike, Katherine Schon, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Patrick May, David Beeson, Judith Cossins, Simone Furini, Alexandra Afenjar, Alice Goldenberg, Alice Masurel, Alice Phan, Anne Dieux-Coeslier, Anne Fargeot, Anne-Marie Guerrot, Annick Toutain, Arnaud Molin, Arthur Sorlin, Audrey Putoux, Béatrice Jouret, Béatrice Laudier, Bénédicte Demeer, Bérénice Doray, Bertille Bonniaud, Bertrand Isidor, Brigitte Gilbert-Dussardier, Bruno Leheup, Bruno Reversade, Carle Paul, Catherine Vincent-Delorme, Cecilia Neiva, Céline Poirsier, Chloé Quélin, Christine Chiaverini, Christine Coubes, Christine Francannet, Cindy Colson, Claire Desplantes, Constance Wells, Cyril Goizet, Damien Sanlaville, Daniel Amram, Daphné Lehalle, David Geneviève, Dominique Gaillard, Einat Zivi, Elisabeth Sarrazin, Elisabeth Steichen, Élise Schaefer, Elodie Lacaze, Emmanuel Jacquemin, Ernie Bongers, Esra Kilic, Estelle Colin, Fabienne Giuliano, Fabienne Prieur, Fanny Laffargue, Fanny Morice-Picard, Florence Petit, François Cartault, François Feillet, Geneviève Baujat, Gilles Morin, Gwenaëlle Diene, Hubert Journel, Isabelle Perthus, James Lespinasse, Jean-Luc Alessandri, Jeanne Amiel, Jelena Martinovic, Julian Delanne, Juliette Albuisson, Laëtitia Lambert, Laurence Perrin, Lilian Bomme Ousager, Lionel Van Maldergem, Lucile Pinson, Lyse Ruaud, Mahtab Samimi, Marie Bournez, Marie Noëlle Bonnet-Dupeyron, Marie Vincent, Marie-Line Jacquemont, Marie-Pierre Cordier-Alex, Marion Gérard-Blanluet, Marjolaine Willems, Marta Spodenkiewicz, Martine Doco-Fenzy, Massimiliano Rossi, Mathilde Renaud, Mélanie Fradin, Michèle Mathieu, Muriel H Holder-Espinasse, Nada Houcinat, Nadine Hanna, Nathalie Leperrier, Nicolas Chassaing, Nicole Philip, Odile Boute, Philippe Khau Van Kien, Philippe Parent, Pierre Bitoun, Pierre Sarda, Pierre Vabres, Pierre-Simon Jouk, Renaud Touraine, Salima El Chehadeh, Sandra Whalen, Sandrine Marlin, Sandrine Passemard, Sarah Grotto, Séverine Audebert Bellanger, Sophie Blesson, Sophie Nambot, Sophie Naudion, Stanislas Lyonnet, Sylvie Odent, Tania Attie-Bitach, Tiffany Busa, Valérie Drouin-Garraud, Valérie Layet, Varoona Bizaoui, Véronica Cusin, Yline Capri, Yves AlembikPurpose: 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.
Funding
The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257.
History
Author affiliation
College of Life Sciences Genetics, Genome Biology & Cancer SciencesVersion
- VoR (Version of Record)
