Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

著者: Leslie Matalonga, Carles Hernandéz-Ferrer, Davide Piscia, Solve-RD SNV-indel working group, Enzo Cohen, Isabel Cuesta, Daniel Danis, Anne‐Sophie Denommé‐Pichon, Yannis Duffourd, Christian Gilissen, Mridul Johari, Steven Laurie, Shuang Li, Leslie Matalonga, Isabelle Nelson, Sophia Peters, Ida Paramonov, Prasanth Sivakumar, Peter N. Robinson, Karolis Sablauskas, Marco Savarese, Wouter Steyaert, Joeri K. van der Velde, Antonio Vitobello, Rebecca Schüle, Matthis Synofzik, Ana Töpf, Lisenka E.L.M. Vissers, Richarda de Voer, Solve-RD DITF-GENTURIS, Stefan Aretz, Gabriel Capellá, Richarda M. de Voer, D. Gareth Evans, Jose Garcia Pelaez, Elke Holinski‐Feder, Nicoline Hoogerbrugge, Andreas Laner, Carla Oliveíra, Andreas Rump, Evelin Schröck, Anna Katharina Sommer, Verena Steinke‐Lange, Iris te Paske, Marc Tischkowitz, Laura Valle, Solve-RD DITF-ITHACA, Siddharth Banka, Elisa Benetti, Giorgio Casari, Andrea Ciolfi, Jill Clayton-Smith, Bruno Dallapiccola, Elke de Boer, Anne‐Sophie Denommé‐Pichon, Kornelia Ellwanger, Laurence Faivre, Holm Graessner, Tobias B. Haack, Anna Hammarsjö, Markéta Havlovičová, Alexander Hoischen, Anne Hugon, Adam Jackson, Tjitske Kleefstra, Anna Lindstrand, Estrella López‐Martín, Milan Macek, Manuela Morleo, Vicenzo Nigro, Ann Nordgren, Maria Pettersson, Michele Pinelli, Simone Pizzi, Manuel Posada, Francesca Clementina Radio, Alessandra Renieri, Caroline Rooryck, Lukáš Ryba, Martin Schwarz, Marco Tartaglia, Christel Thauvin, Annalaura Torella, Aurélien Trimouille, Alain Verloès, Lisenka E.L.M. Vissers, Antonio Vitobello, Pavel Votýpka, Klea Vyshka, Birte Zurek, Solve-RD DITF-euroNMD, Jonathan Baets, Danique Beijer, Gisèle Bonne, Enzo Cohen, Judith Cossins, Teresinha Evangelista, Alessandra Ferlini, Peter Hackman, Michael G. Hanna, Rita Horvath, Henry Houlden, Mridul Johari, Jarred Lau, Hanns Lochmüller, William L. Macken, Francesco Musacchia, A. Nascimento, Daniel Natera‐de Benito, Vincenzo Nigro, Giulio Piluso, Veronica Pini, Robert D. S. Pitceathly, Kiran Polavarapu, Pedro M. Rodríguez Cruz, Anna Sarkozy, Marco Savarese, Rita Selvatici, Rachel Thompson, Bjarne Udd, Liedewei Van de Vondel, Jana Vandrovcova, Irina Zaharieva, Solve-RD DITF-RND, Jonathan Baets, Peter Balicza, Patrick F. Chinnery, Alexandra Dürr, Tobias B. Haack, Holger Hengel, Henry Houlden, Erik-Jan Kamsteeg, Christoph Kamsteeg, Katja Lohmann, Alfons Macaya, Anna Marcé-Grau, Ales Maver, Judit Molnar, Alexander Münchau, Borut Peterlin, Olaf Rieß, Lüdger Schöls, Rebecca Schüle, Giovanni Stévanin, Matthis Synofzik, Vincent Timmerman, Bart van de Warrenburg, Nienke van Os, Melanie Wayand, Carlo Wilke, Raúl Tonda, Steven Laurie, Marcos Fernandez-Callejo, Daniel Picó, Carles Garcia-Linares, Anastasios Papakonstantinou, Alberto Corvò, Ricky S. Joshi, Hector Diez, Marta Gut, Alexander Hoischen, Holm Graessner, Sergi Beltran, the Solve-RD Consortia, Tobias B. Haack, Holm Graeßner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze‐Hentrich, Rebecca Schüle, Christoph Keßler, Melanie Wayand, Lüdger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Peter A.C. ’t Hoen, Wouter Steyaert, Karolis Sablauskas, Erik-Jan Kamsteeg, Bart van de Warrenburg, Iris te Paske, Erik Janssen, Marloes Steehouwer, Burcu Yaldız, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Volker Straub, C. Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Yannis Duffourd, Émilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Marta Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvò, Carles García, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros‐Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Alexandra Dürr, Claire-Sophie Davoine, Léna Guillot‐Noël, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Métay, B. Eymard, Enzo Cohen, António Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Věra Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary M. Reilly, Jana Vandrovcova, Francesco Muntoni, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter De Jonghe, Sandro Banfi, Annalaura Torella, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, 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, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Caroline Rooryck, Aurélien Trimouille, Raffaele Castello, Manuela Morleo, Alessandra Varavallo, Manuel Posada de la Paz, Eva Bermejo, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Mária Judit Molnár, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje G. Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera‐de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodríguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capellá, Laura Valle, Elke Holinski‐Feder, Andreas Laner, Verena Steinke‐Lange, Evelin Schröck, Andreas Rump - European Journal of Human Genetics 2021 被引用: 74

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.