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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

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 K van Der Velde , Ana Töpf , Richarda M de Voer , Gareth Evans , Anna Katharina Sommer , Iris Te 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 E L M Vissers , Antonio Vitobello (5, 4) , Pavel Votypka , Klea Vyshka , Michael G Hanna , Jarred Lau , William L Macken , Francesco Musacchia , Andres Nascimento , Daniel Natera-de Benito , Vincenzo Nigro , Giulio Piluso , Veronica Pini , Robert D S 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 B Haack , Holm Graessner , Birte Zurek , Kornelia Ellwanger , Stephan Ossowski , German Demidov , Marc Sturm , Julia M Schulze-Hentrich , Rebecca Schüle , Christoph Kessler , Melanie Wayand , Ludger 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 Yaldiz , Anthony J 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 (5, 4) , Christel Thauvin (5, 4) , Yannis Duffourd (5, 4) , Emilie Tisserant , Ange-Line Bruel , Christine Peyron , Aurore Pélissier , Sergi Beltran , Ivo Glynne 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 Ben Yaou (7) , Corinne Metay (7) , Bruno Eymard (7) , Enzo Cohen (7) , Antonio Atalaia (7) , Tanya Stojkovic (7) , Milan Macek , Marek Turnovec , Dana Thomasová , Radka Pourová 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 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 Sánchez , Estrella López Martín , Beatriz Martínez Delgado , F. Javier Alonso García 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 M Rodriguez 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
Anna Katharina Sommer
  • Function : Author
Iris Te Paske
  • Function : Author
Farid Yavari Dizjikan
  • Function : Author
Chiara Marini Bettolo
  • Function : Author
Ivo Glynne Gut
  • Function : Author
Rabah Ben Yaou
  • Function : Author
Radka Pourová Kremliková
  • Function : Author
Jose Garcia Pelaez
  • Function : Author
Ana Rita Matos
  • Function : Author
Celina São José
  • Function : Author
Manuel Posada de La Paz
  • Function : Author
Eva Bermejo Sánchez
  • Function : Author
Estrella López Martín
  • Function : Author
Beatriz Martínez Delgado
  • Function : Author
Francesca Clementina Radio
  • Function : Author
Maria Judit Molnar
  • Function : Author
Andres Nascimiento Osorio
  • Function : Author
Daniel Natera de Benito
  • Function : Author
Shuang Li
  • Function : Author
  • PersonId : 772822
  • IdRef : 191915882
Sivakumar Prasanth
  • Function : Author
Peter Robinson
  • Function : Author
Joeri K van Der Velde
  • Function : Author
Ana Töpf
  • Function : Author
Richarda M de Voer
  • Function : Author
Gareth Evans
  • Function : Author
Anna Katharina Sommer
  • Function : Author
Iris Te Paske
  • Function : Author
Marc Tischkowitz
  • Function : Author
Giorgio Casari
Andrea Ciolfi
  • Function : Author
Bruno Dallapiccola
  • Function : Author
Elke de Boer
  • Function : Author
Anna Hammarsjö
  • Function : Author
Anne Hugon
  • Function : Author
Tjitske Kleefstra
  • Function : Author
Anna Lindstrand
  • Function : Author
Estrella López-Martín
  • 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
Lukas Ryba
  • Function : Author
Martin Schwarz
  • Function : Author
Alain Verloes
Lisenka E L M Vissers
  • Function : Author
Pavel Votypka
  • Function : Author
Klea Vyshka
  • Function : Author
Michael G Hanna
  • Function : Author
Jarred Lau
  • Function : Author
William L Macken
  • Function : Author
Francesco Musacchia
  • Function : Author
Andres Nascimento
  • Function : Author
Daniel Natera-de Benito
  • Function : Author
Vincenzo Nigro
  • Function : Author
Giulio Piluso
  • Function : Author
Veronica Pini
  • Function : Author
Robert D S Pitceathly
  • Function : Author
Irina Zaharieva
  • Function : Author
Patrick Chinnery
  • Function : Author
Christoph Kamsteeg
  • Function : Author
Judit Molnar
  • Function : Author
Olaf Riess
  • Function : Author
Rebecca Schüle-Freyer
  • Function : Author
Giovanni Stevanin
Matthis Synofzik
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Nienke van Os
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Carlo Wilke
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Raul Tonda
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Carles Garcia-Linares
  • Function : Author
Ricky Joshi
  • Function : Author
Hector Diez
  • Function : Author
Alexander Hoischen
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Tobias B 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 M Schulze-Hentrich
  • Function : Author
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 a C ’t Hoen
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Wouter Steyaert
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Karolis Sablauskas
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Erik-Jan Kamsteeg
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Bart van de Warrenburg
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Iris Te Paske
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Erik Janssen
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Marloes Steehouwer
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Burcu Yaldiz
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Anthony J Brookes
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Colin Veal
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Spencer Gibson
  • Function : Author
Marc Wadsley
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Mehdi Mehtarizadeh
  • Function : Author
Umar Riaz
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Greg Warren
  • Function : Author
Farid Yavari Dizjikan
  • Function : Author
Thomas Shorter
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Volker Straub
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Chiara Marini Bettolo
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Sabine Specht
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Jill Clayton-Smith
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Siddharth Banka
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Elizabeth Alexander
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Adam Jackson
Emilie Tisserant
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  • PersonId : 770121
  • IdRef : 159351952
Ange-Line Bruel
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Christine Peyron
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Aurore Pélissier
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Sergi Beltran
  • Function : Author
Ivo Glynne Gut
  • Function : Author
Steven Laurie
  • Function : Author
Anastasios Papakonstantinou
  • Function : Author
Gemma Bullich
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Alberto Corvó
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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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Gulcin Gumus
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Virginie Bros-Facer
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Ana Rath
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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 Dürr
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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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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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Marketa Havlovicova
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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
  • Function : Author
Christine Patch
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Mike Hanna
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Henry Houlden
Mary Reilly
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Jana Vandrovcova
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Francesco Muntoni
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
Alessandra Ferlini
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Rita Selvatici
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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
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Carla Oliveira
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Jose Garcia Pelaez
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Ana Rita Matos
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Celina São José
  • Function : Author
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 A Swertz
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Lennart Johansson
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Gerben van Der Vries
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Pieter B 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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Aurélien 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
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Estrella López Martín
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Beatriz Martínez Delgado
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Francesca Clementina Radio
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Marco Tartaglia
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Alessandra Renieri
Elisa Benetti
Peter Balicza
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Maria Judit Molnar
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Ales Maver
  • Function : Author
Borut Peterlin
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Alexander Münchau
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Katja Lohmann
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Rebecca Herzog
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Martje Pauly
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Alfons Macaya
  • Function : Author
Anna Marcé-Grau
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Andres Nascimiento Osorio
  • Function : Author
Daniel Natera de Benito
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Hanns Lochmüller
Rachel Thompson
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Kiran Polavarapu
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David Beeson
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Judith Cossins
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Pedro M Rodriguez Cruz
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Peter Hackman
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Marco Savarese
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Bjarne Udd
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Rita Horvath
Gabriel Capella
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Laura Valle
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Elke Holinski-Feder
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Andreas Laner
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Verena Steinke-Lange
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Evelin Schröck
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Andreas Rump
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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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Origin : Publication funded by an institution

Dates and versions

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

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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, 2021, 29 (9), pp.1337 - 1347. ⟨10.1038/s41431-021-00852-7⟩. ⟨hal-03352530v2⟩
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