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Journal Articles European Journal of Human Genetics Year : 2021

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

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

Domains

Genetics

Dates and versions

hal-03352530 , version 2 (23-09-2021)
hal-03352530 , version 1 (08-11-2022)

Identifiers

Cite

Leslie Matalonga, Carles Hernández-Ferrer, Davide Piscia, Enzo Cohen, Isabel Cuesta, et al.. Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. European Journal of Human Genetics, 2021, 29 (9), pp.1337-1347. ⟨10.1038/s41431-021-00852-7⟩. ⟨hal-03352530v1⟩
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