Solving patients with rare diseases through programmatic reanalysis of genome-phenome data
Authors: Matalonga Leslie , Hernández-Ferrer Carles , Piscia Davide ,   Solve-RD SNV-indel working group, Cohen Enzo , Cuesta Isabel , Danis Daniel , Denommé-Pichon Anne-Sophie , Duffourd Yannis , Gilissen Christian , Johari Mridul , Laurie Steven , Li Shuang , Matalonga Leslie , Nelson Isabelle , Peters Sophia , Paramonov Ida , Prasanth Sivakumar , Robinson Peter , Sablauskas Karolis , Savarese Marco , Steyaert Wouter , van der Velde Joeri K. , Vitobello Antonio , Schüle Rebecca , Synofzik Matthis , Töpf Ana , Vissers Lisenka E. L. M. , de Voer Richarda ,   Solve-RD DITF-GENTURIS, 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 ,   Solve-RD DITF-ITHACA, 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 ,   Solve-RD DITF-euroNMD, Baets Jonathan , Beijer Danique , Bonne Gisèle , Cohen Enzo , 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 ,   Solve-RD DITF-RND, Baets Jonathan , Balicza Peter , Chinnery Patrick , Dürr Alexandra , Haack Tobias , Hengel Holger , Houlden Henry , 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 , 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 ,   the Solve-RD Consortia, Haack Tobias B. , Graessner Holm , Zurek Birte , Ellwanger Kornelia , Ossowski Stephan , Demidov German , Sturm Marc , Schulze-Hentrich Julia M. , Schüle Rebecca , Kessler Christoph , Wayand Melanie , Schöls Ludger , Hengel Holger , Heutink Peter , Brunner Han , Scheffer Hans , Hoogerbrugge Nicoline , ’t Hoen Peter A. C. , Steyaert Wouter , Sablauskas Karolis , Kamsteeg Erik-Jan , 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 , Duffourd Yannis , 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 , Bonne Gisèle , Evangelista Teresinha , Allamand Valérie , Nelson Isabelle , Yaou Rabah Ben , Metay Corinne , Eymard Bruno , Cohen Enzo , 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 , Danis Daniel , Robert Glenn , Costa Alessia , Patch Christine , Hanna Mike , Houlden Henry , Reilly Mary , Vandrovcova Jana , Muntoni Francesco , Sarkozy Anna , Timmerman Vincent , Baets Jonathan , Van de Vondel Liedewei , Beijer Danique , de Jonghe Peter , Banfi Sandro , Torella Annalaura , Ferlini Alessandra , Selvatici Rita , Rossi Rachele , Neri Marcella , Aretz Stefan , Spier Isabel , 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. , Roelofs-Prins Dieuwke , Köhler Sebastian , Metcalfe Alison , Rooryck Caroline , Trimouille Aurelien , Castello Raffaele , Morleo Manuela , 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 , Tartaglia Marco , Renieri Alessandra , Benetti Elisa , 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 , Rump Andreas 
Published: June 2021

AbstractReanalysis 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.