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

MATALONGA, Leslie, HERNÁNDEZ-FERRER, Carles, PISCIA, Davide, SCHÜLE, Rebecca, SYNOFZIK, Matthis, TÖPF, Ana, VISSERS, Lisenka E. L. M., DE VOER, Richarda, TONDA, Raul, LAURIE, Steven, FERNANDEZ-CALLEJO, Marcos, PICÓ, Daniel, GARCIA-LINARES, Carles, PAPAKONSTANTINOU, Anastasios, CORVÓ, Alberto, JOSHI, Ricky, DIEZ, Hector, GUT, Ivo, HOISCHEN, Alexander, GRAESSNER, Holm, BELTRAN, Sergi, COHEN, Enzo, CUESTA, Isabel, DANIS, Daniel, DENOMMÉ-PICHON, Anne-Sophie, DUFFOURD, Yannis, GILISSEN, Christian, JOHARI, Mridul, LI, Shuang, NELSON, Isabelle, PETERS, Sophia, PARAMONOV, Ida, PRASANTH, Sivakumar, ROBINSON, Peter, SABLAUSKAS, Karolis, SAVARESE, Marco, STEYAERT, Wouter, VAN DER VELDE, Joeri K., VITOBELLO, Antonio, ARETZ, Stefan, CAPELLA, Gabriel, DE VOER, Richarda M., EVANS, Gareth, PELAEZ, Jose Garcia, HOLINSKI-FEDER, Elke, HOOGERBRUGGE, Nicoline, LANER, Andreas, OLIVEIRA, Carla, RUMP, Andreas, SCHRÖCK, Evelin, SOMMER, Anna Katharina, STEINKE-LANGE, Verena, PASKE, Iris te, TISCHKOWITZ, Marc, VALLE, Laura, BANKA, Siddharth, BENETTI, Elisa, CASARI, Giorgio, CIOLFI, Andrea, CLAYTON-SMITH, Jill, DALLAPICCOLA, Bruno, DE BOER, Elke, DENOMMÉ-PICHON, Anne-Sophie, ELLWANGER, Kornelia, FAIVRE, Laurence, GRAESSNER, Holm, HAACK, Tobias B., HAMMARSJÖ, Anna, HAVLOVICOVA, Marketa, HOISCHEN, Alexander, HUGON, Anne, JACKSON, Adam, KLEEFSTRA, Tjitske, LINDSTRAND, Anna, LÓPEZ-MARTÍN, Estrella, MACEK, Milan, MORLEO, Manuela, NIGRO, Vicenzo, NORDGREN, Ann, PETTERSSON, Maria, PINELLI, Michele, PIZZI, Simone, POSADA, Manuel, RADIO, Francesca Clementina, RENIERI, Alessandra, ROORYCK, Caroline, RYBA, Lukas, SCHWARZ, Martin, TARTAGLIA, Marco, THAUVIN, Christel, TORELLA, Annalaura, TRIMOUILLE, Aurélien, VERLOES, Alain, VISSERS, Lisenka, VITOBELLO, Antonio, VOTYPKA, Pavel, VYSHKA, Klea, ZUREK, Birte, BAETS, Jonathan, BEIJER, Danique, BONNE, Gisèle, COSSINS, Judith, EVANGELISTA, Teresinha, FERLINI, Alessandra, HACKMAN, Peter, HANNA, Michael G., HORVATH, Rita, HOULDEN, Henry, JOHARI, Mridul, LAU, Jarred, LOCHMÜLLER, Hanns, MACKEN, William L., MUSACCHIA, Francesco, NASCIMENTO, Andres, NATERA-DE BENITO, Daniel, NIGRO, Vincenzo, PILUSO, Giulio, PINI, Veronica, PITCEATHLY, Robert D. S., POLAVARAPU, Kiran, CRUZ, Pedro M. Rodriguez, SARKOZY, Anna, SAVARESE, Marco, SELVATICI, Rita, THOMPSON, Rachel, UDD, Bjarne, VAN DE VONDEL, Liedewei, VANDROVCOVA, Jana, ZAHARIEVA, Irina, BAETS, Jonathan, BALICZA, Peter, CHINNERY, Patrick, DÜRR, Alexandra, HAACK, Tobias, HENGEL, Holger, KAMSTEEG, Erik-Jan, KAMSTEEG, Christoph, LOHMANN, Katja, MACAYA, Alfons, MARCÉ-GRAU, Anna, MAVER, Ales, MOLNAR, Judit, MÜNCHAU, Alexander, PETERLIN, Borut, RIESS, Olaf, SCHÖLS, Ludger, SCHÜLE-FREYER, Rebecca, STEVANIN, Giovanni, SYNOFZIK, Matthis, TIMMERMAN, Vincent, VAN DE WARRENBURG, Bart, VAN OS, Nienke, WAYAND, Melanie, WILKE, Carlo, GRAESSNER, Holm, OSSOWSKI, Stephan, DEMIDOV, German, STURM, Marc, SCHULZE-HENTRICH, Julia M., SCHÜLE, Rebecca, KESSLER, Christoph, HEUTINK, Peter, BRUNNER, Han, SCHEFFER, Hans, ’T HOEN, Peter A. C., SABLAUSKAS, Karolis, VAN DE WARRENBURG, Bart, TE PASKE, Iris, JANSSEN, Erik, STEEHOUWER, Marloes, YALDIZ, Burcu, BROOKES, Anthony J., VEAL, Colin, GIBSON, Spencer, WADSLEY, Marc, MEHTARIZADEH, Mehdi, RIAZ, Umar, WARREN, Greg, DIZJIKAN, Farid Yavari, SHORTER, Thomas, STRAUB, Volker, BETTOLO, Chiara Marini, SPECHT, Sabine, CLAYTON-SMITH, Jill, BANKA, Siddharth, ALEXANDER, Elizabeth, JACKSON, Adam, FAIVRE, Laurence, THAUVIN, Christel, TISSERANT, Emilie, BRUEL, Ange-Line, PEYRON, Christine, PÉLISSIER, Aurore, BELTRAN, Sergi, GUT, Ivo Glynne, LAURIE, Steven, PISCIA, Davide, MATALONGA, Leslie, PAPAKONSTANTINOU, Anastasios, BULLICH, Gemma, CORVO, Alberto, GARCIA, Carles, FERNANDEZ-CALLEJO, Marcos, HERNÁNDEZ, Carles, PICÓ, Daniel, PARAMONOV, Ida, LOCHMÜLLER, Hanns, GUMUS, Gulcin, BROS-FACER, Virginie, RATH, Ana, HANAUER, Marc, OLRY, Annie, LAGORCE, David, HAVRYLENKO, Svitlana, IZEM, Katia, RIGOUR, Fanny, DURR, Alexandra, DAVOINE, Claire-Sophie, GUILLOT-NOEL, Léna, HEINZMANN, Anna, COARELLI, Giulia, ALLAMAND, Valérie, YAOU, Rabah Ben, METAY, Corinne, EYMARD, Bruno, ATALAIA, Antonio, STOJKOVIC, Tanya, MACEK, Milan, TURNOVEC, Marek, THOMASOVÁ, Dana, KREMLIKOVÁ, Radka Pourová, FRANKOVÁ, Vera, HAVLOVICOVÁ, Markéta, KREMLIK, Vlastimil, PARKINSON, Helen, KEANE, Thomas, SPALDING, Dylan, SENF, Alexander, ROBERT, Glenn, COSTA, Alessia, PATCH, Christine, HANNA, Mike, HOULDEN, Henry, REILLY, Mary, VANDROVCOVA, Jana, MUNTONI, Francesco, VAN DE VONDEL, Liedewei, BEIJER, Danique, DE JONGHE, Peter, BANFI, Sandro, TORELLA, Annalaura, ROSSI, Rachele, NERI, Marcella, SPIER, Isabel, 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., ROELOFS-PRINS, Dieuwke, KÖHLER, Sebastian, METCALFE, Alison, TRIMOUILLE, Aurelien, CASTELLO, Raffaele, VARAVALLO, Alessandra, DE LA PAZ, Manuel Posada, SÁNCHEZ, Eva Bermejo, MARTÍN, Estrella López, DELGADO, Beatriz Martínez, DE LA ROSA, F. Javier Alonso García, RADIO, Francesca Clementina, BALICZA, Peter, MOLNAR, Maria Judit, MAVER, Ales, PETERLIN, Borut, MÜNCHAU, Alexander, LOHMANN, Katja, HERZOG, Rebecca, PAULY, Martje, MACAYA, Alfons, MARCÉ-GRAU, Anna, OSORIO, Andres Nascimiento, DE BENITO, Daniel Natera, LOCHMÜLLER, Hanns, THOMPSON, Rachel, POLAVARAPU, Kiran, BEESON, David, COSSINS, Judith, CRUZ, Pedro M. Rodriguez, HACKMAN, Peter, JOHARI, Mridul, SAVARESE, Marco, UDD, Bjarne, HORVATH, Rita, CAPELLA, Gabriel, VALLE, Laura, HOLINSKI-FEDER, Elke, LANER, Andreas, STEINKE-LANGE, Verena, SCHRÖCK, Evelin and RUMP, Andreas (2021). Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. European Journal of Human Genetics, 29 (9), 1337-1347.

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Abstract

Abstract: 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.

Item Type:	Article
Additional Information:	** From Springer Nature via Jisc Publications Router ** Licence for this article: http://creativecommons.org/licenses/by/4.0/ **Journal IDs: pissn 1018-4813; eissn 1476-5438 **Article IDs: publisher-id: s41431-021-00852-7; manuscript: 852 **History: published 09-2021; online 01-06-2021; published 01-06-2021; accepted 26-02-2021; registration 26-02-2021; rev-recd 18-01-2021; submitted 13-10-2020
Uncontrolled Keywords:	Article, /692/699, /631/208/2489/1512, /631/114/2785, /631/1647/2217, /45/23, article
Identification Number:	https://doi.org/10.1038/s41431-021-00852-7
Page Range:	1337-1347
SWORD Depositor:	Colin Knott
Depositing User:	Colin Knott
Date Deposited:	16 Sep 2021 10:22
Last Modified:	16 Sep 2021 10:30
URI:	https://shura.shu.ac.uk/id/eprint/29063

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