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

Anna Katharina Sommer Iris Te Paske Farid Yavari Dizjikan Chiara Marini Bettolo Ivo Glynne Gut Rabah Ben Yaou Radka Pourová Kremliková Jose Garcia Pelaez Ana Rita Matos Celina São José Manuel Posada de la Paz Eva Bermejo Sánchez Estrella López Martín Beatriz Martínez Delgado Francesca Clementina Radio Maria Judit Molnar Andres Nascimiento Osorio Daniel Natera de Benito Carles Hernández-Ferrer 1 Isabel Cuesta 2 Christian Gilissen 3 Shuang Li Sivakumar Prasanth Peter Robinson Joeri van der Velde Ana Töpf Richarda de Voer Gareth Evans Anna Sommer Iris Paske Marc Tischkowitz Giorgio Casari Andrea Ciolfi Bruno Dallapiccola Elke de Boer Anne-Sophie Denommé-Pichon 4, 5 Anna Hammarsjö Anne Hugon Tjitske Kleefstra Anna Lindstrand Estrella López-Martín Vicenzo Nigro Ann Nordgren Maria Pettersson Michele Pinelli Simone Pizzi Manuel Posada Lukas Ryba Martin Schwarz Alain Verloes Lisenka Vissers Antonio Vitobello 5, 4 Pavel Votypka Klea Vyshka Michael Hanna Jarred Lau William Macken Francesco Musacchia Andres Nascimento Daniel Natera-de Benito Vincenzo Nigro Giulio Piluso Veronica Pini Robert Pitceathly Irina Zaharieva Patrick Chinnery Christoph Kamsteeg Judit Molnar Olaf Riess Rebecca Schüle-Freyer Giovanni Stevanin Matthis Synofzik Nienke van Os Carlo Wilke Raul Tonda Carles Garcia-Linares Ricky Joshi Hector Diez Alexander Hoischen Tobias Haack Holm Graessner Birte Zurek Kornelia Ellwanger Stephan Ossowski German Demidov Marc Sturm Julia Schulze-Hentrich Rebecca Schüle Christoph Kessler Melanie Wayand Ludger Schöls Holger Hengel Peter Heutink Han Brunner Hans Scheffer Nicoline Hoogerbrugge Peter ’t Hoen Wouter Steyaert Karolis Sablauskas Erik-Jan Kamsteeg Bart van de Warrenburg Iris Te Paske Erik Janssen Marloes Steehouwer Burcu Yaldiz Anthony Brookes Colin Veal Spencer Gibson Marc Wadsley Mehdi Mehtarizadeh Umar Riaz Greg Warren Farid Dizjikan Thomas Shorter Volker Straub Chiara Bettolo Sabine Specht Jill Clayton-Smith Siddharth Banka Elizabeth Alexander Adam Jackson Laurence Faivre 5, 4 Christel Thauvin 5, 4 Yannis Duffourd 5, 4 Emilie Tisserant Ange-Line Bruel Christine Peyron Aurore Pélissier Sergi Beltran Ivo Gut Steven Laurie Davide Piscia 6 Leslie Matalonga 6 Anastasios Papakonstantinou Gemma Bullich Alberto Corvó Carles Garcia Marcos Fernandez-Callejo Carles Hernández Daniel Picó Ida Paramonov 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-Noel Anna Heinzmann Giulia Coarelli Gisèle Bonne 7 Teresinha Evangelista 7 Valérie Allamand 7 Isabelle Nelson 7 Rabah Yaou 7 Corinne Metay 7 Bruno Eymard 7 Enzo Cohen 7 Antonio Atalaia 7 Tanya Stojkovic 7 Milan Macek Marek Turnovec Dana Thomasová Radka Kremliková Vera Franková Marketa Havlovicova Vlastimil Kremlik Helen Parkinson Thomas Keane Dylan Spalding Alexander Senf Daniel Danis Glenn Robert Alessia Costa Christine Patch Mike Hanna Henry Houlden Mary 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 Pelaez Ana Matos Celina José Marta Ferreira Irene Gullo Susana Fernandes Luzia Garrido Pedro Ferreira Fátima Carneiro Morris Swertz Lennart Johansson Gerben van der Vries Pieter Neerincx Dieuwke Roelofs-Prins Sebastian Köhler Alison Metcalfe Caroline Rooryck Aurélien Trimouille Raffaele Castello Manuela Morleo Alessandra Varavallo Manuel de la Paz Eva Sánchez Estrella Martín Beatriz Delgado F. Javier Alonso García de la Rosa Francesca Radio Marco Tartaglia Alessandra Renieri Elisa Benetti Peter Balicza Maria Molnar Ales Maver Borut Peterlin Alexander Münchau Katja Lohmann Rebecca Herzog Martje Pauly Alfons Macaya Anna Marcé-Grau Andres Osorio Daniel de Benito Hanns Lochmüller Rachel Thompson Kiran Polavarapu David Beeson Judith Cossins Pedro Cruz Peter Hackman Mridul Johari 8 Marco Savarese Bjarne Udd Rita Horvath Gabriel Capella Laura Valle Elke Holinski-Feder Andreas Laner Verena Steinke-Lange Evelin Schröck Andreas Rump
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.
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https://hal.sorbonne-universite.fr/hal-03352530
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Soumis le : jeudi 23 septembre 2021 - 11:50:49
Dernière modification le : mercredi 6 octobre 2021 - 03:16:01

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s41431-021-00852-7.pdf
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Anna Katharina Sommer, Iris Te Paske, Farid Yavari Dizjikan, Chiara Marini Bettolo, Ivo Glynne Gut, et al.. Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. European Journal of Human Genetics, Nature Publishing Group, 2021, 29 (9), pp.1337 - 1347. ⟨10.1038/s41431-021-00852-7⟩. ⟨hal-03352530⟩

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