Title : A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
Language : English
Author, co-author : Denommé-Pichon, Anne-Sophie [> >]
Matalonga, Leslie [> >]
de Boer, Elke [> >]
Jackson, Adam [> >]
Benetti, Elisa [> >]
Banka, Siddharth [> >]
Bruel, Ange-Line [> >]
Ciolfi, Andrea [> >]
Clayton-Smith, Jill [> >]
Dallapiccola, Bruno [> >]
Duffourd, Yannis [> >]
Ellwanger, Kornelia [> >]
Fallerini, Chiara [> >]
Gilissen, Christian [> >]
Graessner, Holm [> >]
Haack, Tobias B. [> >]
Havlovicova, Marketa [> >]
Hoischen, Alexander [> >]
Jean-Marçais, Nolwenn [> >]
Kleefstra, Tjitske [> >]
López-Martín, Estrella [> >]
Macek, Milan [> >]
Mencarelli, Maria Antonietta [> >]
Moutton, Sébastien [> >]
Pfundt, Rolph [> >]
Pizzi, Simone [> >]
Posada, Manuel [> >]
Radio, Francesca Clementina [> >]
Renieri, Alessandra [> >]
Rooryck, Caroline [> >]
Ryba, Lukas [> >]
Safraou, Hana [> >]
Schwarz, Martin [> >]
Tartaglia, Marco [> >]
Thauvin-Robinet, Christel [> >]
Thevenon, Julien [> >]
Tran Mau-Them, Frédéric [> >]
Trimouille, Aurélien [> >]
Votypka, Pavel [> >]
de Vries, Bert B. A. [> >]
Willemsen, Marjolein H. [> >]
Zurek, Birte [> >]
Verloes, Alain [> >]
Philippe, Christophe [> >]
Abbott, Kristin M. [> >]
Faivre, Laurence [> >]
Kerstjens, Mieke [> >]
Martín, Estrella López [> >]
Macek Jr., Milan [> >]
Maystadt, Isabelle [> >]
Morleo, Manuela [> >]
Nigro, Vicenzo [> >]
Pinelli, Michele [> >]
Radio, Francesca C. [> >]
Riess, Olaf [> >]
Agathe, Jean-Madeleine De Sainte [> >]
Santen, Gijs W. E. [> >]
Thauvin, Christel [> >]
Torella, Annalaura [> >]
Vissers, Lisenka [> >]
Vitobello, Antonio [> >]
Zguro, Kristina [> >]
Boer, Elke De [> >]
Cohen, Enzo [> >]
Danis, Daniel [> >]
Gao, Fei [> >]
Horvath, Rita [> >]
Johari, Mridul [> >]
Johanson, Lennart [> >]
Li, Shuang [> >]
Morsy, Heba [> >]
Nelson, Isabelle [> >]
Paramonov, Ida [> >]
te Paske, Iris B. A. W. [> >]
Robinson, Peter [> >]
Savarese, Marco [> >]
Steyaert, Wouter [> >]
Töpf, Ana [> >]
van der Velde, Joeri K. [> >]
Vandrovcova, Jana [> >]
Ossowski, Stephan [> >]
Demidov, German [> >]
Sturm, Marc [> >]
Schulze-Hentrich, Julia M. [> >]
Schüle, Rebecca [> >]
Xu, Jishu [> >]
Kessler, Christoph [> >]
Wayand, Melanie [> >]
Synofzik, Matthis [> >]
Wilke, Carlo [> >]
Traschütz, Andreas [> >]
Schöls, Ludger [> >]
Hengel, Holger [> >]
Lerche, Holger [> >]
Kegele, Josua [> >]
Heutink, Peter [> >]
Brunner, Han [> >]
Scheffer, Hans [> >]
Hoogerbrugge, Nicoline [> >]
`t Hoen, Peter A. C. [> >]
Vissers, Lisenka E. L. M. [> >]
Sablauskas, Karolis [> >]
de Voer, Richarda M. [> >]
Kamsteeg, Erik-Jan [> >]
van de Warrenburg, Bart [> >]
van Os, Nienke [> >]
Paske, Iris Te [> >]
Janssen, Erik [> >]
Steehouwer, Marloes [> >]
Yaldiz, Burcu [> >]
Brookes, Anthony J. [> >]
Veal, Colin [> >]
Gibson, Spencer [> >]
Maddi, Vatsalya [> >]
Mehtarizadeh, Mehdi [> >]
Riaz, Umar [> >]
Warren, Greg [> >]
Dizjikan, Farid Yavari [> >]
Shorter, Thomas [> >]
Straub, Volker [> >]
Bettolo, Chiara Marini [> >]
Manera, Jordi Diaz [> >]
Hambleton, Sophie [> >]
Engelhardt, Karin [> >]
Alexander, Elizabeth [> >]
Peyron, Christine [> >]
Pélissier, Aurore [> >]
Beltran, Sergi [> >]
Gut, Ivo Glynne [> >]
Laurie, Steven [> >]
Piscia, Davide [> >]
Papakonstantinou, Anastasios [> >]
Bullich, Gemma [> >]
Corvo, Alberto [> >]
Fernandez-Callejo, Marcos [> >]
Hernández, Carles [> >]
Picó, Daniel [> >]
Lochmüller, Hanns [> >]
Gumus, Gulcin [> >]
Bros-Facer, Virginie [> >]
Rath, Ana [> >]
Hanauer, Marc [> >]
Lagorce, David [> >]
Hongnat, Oscar [> >]
Chahdil, Maroua [> >]
Lebreton, Emeline [> >]
Stevanin, Giovanni [> >]
Durr, Alexandra [> >]
Davoine, Claire-Sophie [> >]
Guillot-Noel, Léna [> >]
Heinzmann, Anna [> >]
Coarelli, Giulia [> >]
Bonne, Gisèle [> >]
Evangelista, Teresinha [> >]
Allamand, Valérie [> >]
Ben Yaou, Rabah [> >]
Metay, Corinne [> >]
Eymard, Bruno [> >]
Atalaia, Antonio [> >]
Stojkovic, Tanya [> >]
Turnovec, Marek [> >]
Thomasová, Dana [> >]
Kremliková, Radka Pourová [> >]
Franková, Vera [> >]
Havlovicová, Markéta [> >]
Li\vsková, Petra [> >]
Dole\vzalová, Pavla [> >]
Parkinson, Helen [> >]
Keane, Thomas [> >]
Freeberg, Mallory [> >]
Thomas, Coline [> >]
Spalding, Dylan [> >]
Robert, Glenn [> >]
Costa, Alessia [> >]
Patch, Christine [> >]
Hanna, Mike [> >]
Houlden, Henry [> >]
Reilly, Mary [> >]
Efthymiou, Stephanie [> >]
Cali, Elisa [> >]
Magrinelli, Francesca [> >]
Sisodiya, Sanjay M. [> >]
Rohrer, Jonathan [> >]
Muntoni, Francesco [> >]
Zaharieva, Irina [> >]
Sarkozy, Anna [> >]
Timmerman, Vincent [> >]
Baets, Jonathan [> >]
de Vries, Geert [> >]
De Winter, Jonathan [> >]
Beijer, Danique [> >]
de Jonghe, Peter [> >]
Van de Vondel, Liedewei [> >]
De Ridder, Willem [> >]
Weckhuysen, Sarah [> >]
Nigro, Vincenzo [> >]
Mutarelli, Margherita [> >]
Varavallo, Alessandra [> >]
Banfi, Sandro [> >]
Musacchia, Francesco [> >]
Piluso, Giulio [> >]
Ferlini, Alessandra [> >]
Selvatici, Rita [> >]
Gualandi, Francesca [> >]
Bigoni, Stefania [> >]
Rossi, Rachele [> >]
Neri, Marcella [> >]
Aretz, Stefan [> >]
Spier, Isabel [> >]
Sommer, Anna Katharina [> >]
Peters, Sophia [> >]
Oliveira, Carla [> >]
Pelaez, Jose Garcia [> >]
Matos, Ana Rita [> >]
José, Celina São [> >]
Ferreira, Marta [> >]
Gullo, Irene [> >]
Fernandes, Susana [> >]
Garrido, Luzia [> >]
Ferreira, Pedro [> >]
Carneiro, Fátima [> >]
Swertz, Morris A. [> >]
Johansson, Lennart [> >]
van der Vries, Gerben [> >]
Neerincx, Pieter B. [> >]
Ruvolo, David [> >]
Kerstjens Frederikse, Wilhemina S. [> >]
Zonneveld-Huijssoon, Eveline [> >]
Roelofs-Prins, Dieuwke [> >]
van Gijn, Marielle [> >]
Köhler, Sebastian [> >]
Metcalfe, Alison [> >]
Drunat, Séverine [> >]
Heron, Delphine [> >]
Mignot, Cyril [> >]
Keren, Boris [> >]
Lacombe, Didier [> >]
Trimouille, Aurelien [> >]
Capella, Gabriel [> >]
Valle, Laura [> >]
Holinski-Feder, Elke [> >]
Laner, Andreas [> >]
Steinke-Lange, Verena [> >]
Cilio, Maria-Roberta [> >]
Carpancea, Evelina [> >]
Depondt, Chantal [> >]
Lederer, Damien [> >]
Sznajer, Yves [> >]
Duerinckx, Sarah [> >]
Mary, Sandrine [> >]
Macaya, Alfons [> >]
Cazurro-Gutiérrez, Ana [> >]
Pérez-Dueñas, Belén [> >]
Munell, Francina [> >]
Jarava, Clara Franco [> >]
Masó, Laura Batlle [> >]
Marcé-Grau, Anna [> >]
Colobran, Roger [> >]
Hackman, Peter [> >]
Udd, Bjarne [> >]
Hemelsoet, Dimitri [> >]
Dermaut, Bart [> >]
Schuermans, Nika [> >]
Poppe, Bruce [> >]
Verdin, Hannah [> >]
Osorio, Andrés Nascimento [> >]
Depienne, Christel [> >]
Roos, Andreas [> >]
Cordts, Isabell [> >]
Deschauer, Marcus [> >]
Striano, Pasquale [> >]
Zara, Federico [> >]
Riva, Antonella [> >]
Iacomino, Michele [> >]
Uva, Paolo [> >]
Scala, Marcello [> >]
Scudieri, Paolo [> >]
Claeys, Kristl [> >]
Boztug, Kaan [> >]
Haimel, Matthias [> >]
W.E, Gijs [> >]
Ruivenkamp, Claudia A. L. [> >]
Natera de Benito, Daniel [> >]
Thompson, Rachel [> >]
Polavarapu, Kiran [> >]
Grimbacher, Bodo [> >]
Zaganas, Ioannis [> >]
Kokosali, Evgenia [> >]
Lambros, Mathioudakis [> >]
Evangeliou, Athanasios [> >]
Spilioti, Martha [> >]
Kapaki, Elisabeth [> >]
Bourbouli, Mara [> >]
Balicza, Peter [> >]
Molnar, Maria Judit [> >]
De la Paz, Manuel Posada [> >]
Sánchez, Eva Bermejo [> >]
Delgado, Beatriz Martínez [> >]
Alonso García de la Rosa, F. Javier [> >]
Schröck, Evelin [> >]
Rump, Andreas [> >]
Mei, Davide [> >]
Vetro, Annalisa [> >]
Balestrini, Simona [> >]
Guerrini, Renzo [> >]
Chinnery, Patrick F. [> >]
Ratnaike, Thiloka [> >]
Schon, Katherine [> >]
Maver, Ales [> >]
Peterlin, Borut [> >]
Münchau, Alexander [> >]
Lohmann, Katja [> >]
Herzog, Rebecca [> >]
Pauly, Martje [> >]
May, Patrick [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Beeson, David [> >]
Cossins, Judith [> >]
Furini, Simone [> >]
Afenjar, Alexandra [> >]
Goldenberg, Alice [> >]
Masurel, Alice [> >]
Phan, Alice [> >]
Dieux-Coeslier, Anne [> >]
Fargeot, Anne [> >]
Guerrot, Anne-Marie [> >]
Toutain, Annick [> >]
Molin, Arnaud [> >]
Sorlin, Arthur [> >]
Putoux, Audrey [> >]
Jouret, Béatrice [> >]
Laudier, Béatrice [> >]
Demeer, Bénédicte [> >]
Doray, Bérénice [> >]
Bonniaud, Bertille [> >]
Isidor, Bertrand [> >]
Gilbert-Dussardier, Brigitte [> >]
Leheup, Bruno [> >]
Reversade, Bruno [> >]
Paul, Carle [> >]
Vincent-Delorme, Catherine [> >]
Neiva, Cecilia [> >]
Poirsier, Céline [> >]
Quélin, Chloé [> >]
Chiaverini, Christine [> >]
Coubes, Christine [> >]
Francannet, Christine [> >]
Colson, Cindy [> >]
Desplantes, Claire [> >]
Wells, Constance [> >]
Goizet, Cyril [> >]
Sanlaville, Damien [> >]
Amram, Daniel [> >]
Lehalle, Daphné [> >]
Geneviève, David [> >]
Gaillard, Dominique [> >]
Zivi, Einat [> >]
Sarrazin, Elisabeth [> >]
Steichen, Elisabeth [> >]
Schaefer, Élise [> >]
Lacaze, Elodie [> >]
Jacquemin, Emmanuel [> >]
Bongers, Ernie [> >]
Kilic, Esra [> >]
Colin, Estelle [> >]
Giuliano, Fabienne [> >]
Prieur, Fabienne [> >]
Laffargue, Fanny [> >]
Morice-Picard, Fanny [> >]
Petit, Florence [> >]
Cartault, François [> >]
Feillet, François [> >]
Baujat, Geneviève [> >]
Morin, Gilles [> >]
Diene, Gwenaëlle [> >]
Journel, Hubert [> >]
Perthus, Isabelle [> >]
Lespinasse, James [> >]
Alessandri, Jean-Luc [> >]
Amiel, Jeanne [> >]
Martinovic, Jelena [> >]
Delanne, Julian [> >]
Albuisson, Juliette [> >]
Lambert, Laëtitia [> >]
Perrin, Laurence [> >]
Ousager, Lilian Bomme [> >]
Van Maldergem, Lionel [> >]
Pinson, Lucile [> >]
Ruaud, Lyse [> >]
Samimi, Mahtab [> >]
Bournez, Marie [> >]
Bonnet-Dupeyron, Marie Noëlle [> >]
Vincent, Marie [> >]
Jacquemont, Marie-Line [> >]
Cordier-Alex, Marie-Pierre [> >]
Gérard-Blanluet, Marion [> >]
Willems, Marjolaine [> >]
Spodenkiewicz, Marta [> >]
Doco-Fenzy, Martine [> >]
Rossi, Massimiliano [> >]
Renaud, Mathilde [> >]
Fradin, Mélanie [> >]
Mathieu, Michèle [> >]
Holder-Espinasse, Muriel H. [> >]
Houcinat, Nada [> >]
Hanna, Nadine [> >]
Leperrier, Nathalie [> >]
Chassaing, Nicolas [> >]
Philip, Nicole [> >]
Boute, Odile [> >]
Van Kien, Philippe Khau [> >]
Parent, Philippe [> >]
Bitoun, Pierre [> >]
Sarda, Pierre [> >]
Vabres, Pierre [> >]
Jouk, Pierre-Simon [> >]
Touraine, Renaud [> >]
El Chehadeh, Salima [> >]
Whalen, Sandra [> >]
Marlin, Sandrine [> >]
Passemard, Sandrine [> >]
Grotto, Sarah [> >]
Bellanger, Séverine Audebert [> >]
Blesson, Sophie [> >]
Nambot, Sophie [> >]
Naudion, Sophie [> >]
Lyonnet, Stanislas [> >]
Odent, Sylvie [> >]
Attie-Bitach, Tania [> >]
Busa, Tiffany [> >]
Drouin-Garraud, Valérie [> >]
Layet, Valérie [> >]
Bizaoui, Varoona [> >]
Cusin, Véronica [> >]
Capri, Yline [> >]
Alembik, Yves [> >]
Publication date : 19-Jan-2023
Journal title : Genetics in Medicine
Publisher : Lippincott Williams & Wilkins
Volume : 25
Issue/season : 4
Pages : 100018
Peer reviewed : Yes
Audience : International
ISSN : 1098-3600
e-ISSN : 1530-0366
Country : United States
Keywords : [en] ClinVar ; Developmental disorder ; Rare diseases ; Exome reanalysis
Abstract : [en] 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.
Research centres : Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Name of the research project : Solve-RD
Target : Researchers ; Professionals
Permalink : http://hdl.handle.net/10993/54941
DOI : 10.1016/j.gim.2023.100018
Other URL : https://doi.org/10.1016/j.gim.2023.100018