Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses
Authors: Demidov German , Yaldiz Burcu , Garcia-Pelaez José , de Boer Elke , Schuermans Nika , Van de Vondel Liedewei , Paramonov Ida , Johansson Lennart F. , Musacchia Francesco , Benetti Elisa , Bullich Gemma , Sablauskas Karolis , Beltran Sergi , Gilissen Christian , Hoischen Alexander , Ossowski Stephan , de Voer Richarda , Lohmann Katja , Oliveira Carla , Topf Ana , Vissers Lisenka E. L. M. ,   Solve-RD Consortium, Riess Olaf , Haack Tobias B. , Graessner Holm , Zurek Birte , Ellwanger Kornelia , Sturm Marc , Park Joohyun , Schütz Leon , Schulze-Hentrich Julia M. , Schüle Rebecca , Xu Jishu , Kellner Melanie , Resch Baptist , Kolen Ingrid , Synofzik Matthis , Wilke Carlo , Traschütz Andreas , Beijer Danique , Heutink Peter , Schöls Ludger , Hengel Holger , Lerche Holger , Boßelmann Christian , Kegele Josua , Lauerer-Braun Robert , Lauxmann Stephan , Brunner Han , Scheffer Hans , Hoogerbrugge Nicoline , ’t Hoen Peter A. C. , Steyaert Wouter , de Voer Richarda , Kamsteeg Erik-Jan , van de Warrenburg Bart , van Os Nienke , Paske Iris te , Janssen Erik , de Boer Elke , Steehouwer Marloes , Neveling Kornelia , van der Sanden Bart , Sagath Lydia , Kleefstra Tjitske , Brookes Anthony J. , Gibson Spencer , Riaz Umar , Warren Greg , Nalagandla Sai Anuhya , Wang Yunze Patrick , Sukumaran Deepthi , Abadijou Sadegh , Straub Volker , Bettolo Chiara Marini , Manera Jordi Diaz , Hambleton Sophie , Engelhardt Karin , Clayton-Smith Jill , Banka Siddharth , Alexander Elizabeth , Jackson Adam , Faivre Laurence , Thauvin Christel , Vitobello Antonio , Denommé-Pichon Anne-Sophie , Duffourd Yannis , Bruel Ange-Line , Couturier Victor , Gut Ivo Glynne , Piscia Davide , Matalonga Leslie , Papakonstantinou Anastasios , Corvo Alberto , Fernandez-Callejo Marcos , Hernández Carles , Picó Daniel , Codina Anna Esteve , Dabad Marc , Gut Marta , Raineri Emanuele , Gumus Gulcin , Bros-Facer Virginie , Rath Ana , Hanauer Marc , Lagorce David , Hongnat Oscar , Chahdil Maroua , Lucano Caterina , Lebreton Emeline , Stevanin Giovanni , Durr Alexandra , Davoine Claire-Sophie , Guillot-Noel Léna , Heinzmann Anna , Coarelli Giulia , Bonne Gisèle , Evangelista Teresinha , Allamand Valérie , Nelson Isabelle , Ben Yaou Rabah , Metay Corinne , Eymard Bruno , Cohen Enzo , Atalaia Antonio , Stojkovic Tanya , Macek Milan , Turnovec Marek , Thomasová Dana , Kremliková Radka Pourová , Franková Vera , Havlovicová Markéta , Ryba Lukáš , Lišková Petra , Doležalová Pavla , Krebsová Alice , Parkinson Helen , Keane Thomas , Freeberg Mallory , Thomas Coline , Spalding Dylan , Robinson Peter , Danis Daniel , Robert Glenn , Costa Alessia , Hanna Mike , Houlden Henry , Reilly Mary , Vandrovcova Jana , Efthymiou Stephanie , Morsy Heba , Cali Elisa , Magrinelli Francesca , Sisodiya Sanjay M. , Bellampalli Ravishankara , Moloney Patrick , Rohrer Jonathan , Muntoni Francesco , Zaharieva Irina , Sarkozy Anna , Perry Luke , Pini Veronica , Müller Juliane , Timmerman Vincent , Baets Jonathan , de Vries Geert , De Winter Jonathan , de Jonghe Peter , Van de Vondel Liedewei , De Ridder Willem , Weckhuysen Sarah , Stamberger Hannah , Millevert Charissa , Smal Noor , Nigro Vincenzo , Morleo Manuela , Pinelli Michele , Banfi Sandro , Torella Annalaura , Zeuli Roberta , Zanobio Mariateresa , Piluso Giulio , Ferlini Alessandra , Selvatici Rita , Gualandi Francesca , Bigoni Stefania , Neri Marcella , Aretz Stefan , Spier Isabel , Sommer Anna Katharina , Peters Sophia , Barbosa-Matos Rita , José Celina São , Ferreira Marta , Gullo Irene , Fernandes Susana , Garrido Luzia , Ferreira Pedro , Carneiro Fátima , Swertz Morris A. , van der Velde Joeri K. , van der Vries Gerben , Neerincx Pieter B. , Roelofs-Prins Dieuwke , Ruvolo David , van Gijn Marielle , Abbott Kristin M. , Kerstjens Frederikse Wilhemina S. , Zonneveld-Huijssoon Eveline , Köhler Sebastian , Metcalfe Alison , Moore Richard , Verloes Alain , Drunat Séverine , Heron Delphine , Mignot Cyril , Keren Boris , de Sainte Agathe Jean-Madeleine , Jamra Rami Abou , Abramowicz Marc , Kiliçarslan Özge Aksel , Allen Nicholas , Javier Alonso García de la Rosa Francisco , Balestrini Simona , Balicza Peter , Bartolomaeus Tobias , Başak Ayşe Nazl , Masó Laura Batlle , Beeson David , Benoit Valerie , Benson Katherine , Sánchez Eva Bermejo , Bijlsma Emilia K. , Bogaert Elke , Bourbouli Mara , Boztug Kaan , Brohée Sylvain , Byrne Susan , Garcia de Oteyza Andrés Caballero , Capella Gabriel , Carpancea Evelina , Cavalleri Gianpiero , Cazurro-Gutiérrez Ana , Chinnery Patrick F. , Cilio Maria-Roberta , Ciolfi Andrea , Claeys Kristl , Colobran Roger , Cordts Isabell , Cossins Judith , Dahan Karin , Dallapiccola Bruno , Delanty Norman , Depienne Christel , Depondt Chantal , Dermaut Bart , Deschauer Marcus , Desir Julie , Destrée Anne , Drakos Minas , Duerinckx Sarah , Estevez Berta , Evangeliou Athanasios , Fallerini Chiara , Ferilli Marco , Furini Simone , Gagneur Julien , Ghani Hamidah , Greally Marie , Grimbacher Bodo , Guerrini Renzo , Hackman Peter , Haimel Matthias , Bouveret Eva Hammar , Hemelsoet Dimitri , Herzog Rebecca , Hoffer Mariette J. V. , Holinski-Feder Elke , Horvath Rita , Huibers Manon , Iacomino Michele , Johari Mridul , Kapaki Elisabeth , Karadurmus Deniz , Karakaya Mert , Kokosali Evgenia , Korff Christian , Krass Leon , Lacombe Didier , Laner Andreas , Leavis Helen , Lederer Damien , Leitão Elsa , Lochmüller Hanns , Martín Estrella López , Luknárová Rebeka , Macaya Alfons , Malaichamy Sivasankar , Marcé-Grau Anna , Delgado Beatriz Martínez , Mary Sandrine , Masclaux Frédéric , Mathioudakis Lambros , Maver Ales , May Patrick , Maystadt Isabelle , Mei Davide , Mertes Christian , Meunier Colombine , Molnar Maria Judit , Monestier Olivier , Moortgat Stéphanie , Münchau Alexander , Munell Francina , Osorio Andrés Nascimento , de Benito Daniel Natera , Reghan Mary O. , Olimpio Catarina , Parrini Elena , Pauly Martje , Pérez-Dueñas Belén , Peterlin Borut , Platzer Konrad , Polavarapu Kiran , Poppe Bruce , De la Paz Manuel Posada , Privitera Flavia , Radio Francesca Clementina , Ratnaike Thiloka , Renieri Alessandra , Riva Antonella , Rooryck Caroline , Roos Andreas , Ruivenkamp Claudia A. L. , Rump Andreas , Santen Gijs W. E. , Savarese Marco , Scala Marcello , Schon Katherine , Schröck Evelin , Scudieri Paolo , Spilioti Martha , Steinke-Lange Verena , Striano Pasquale , Sznajer Yves , Tartaglia Marco , Thompson Rachel , Trimouille Aurelien , Udd Bjarne , Uva Paolo , Valle Laura , van der Veken Lars , van Heurck Roxane , van Montfrans Joris , Van Nieuwenhove Erika , Verdin Hannah , Webb David , Wirth Brunhilde , Yépez Vicente A. , Zaganas Ioannis , Zara Federico , Zguro Kristina , Laurie Steven 
Published: October 2024

We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project. Each research group had previously undertaken their own analysis of the data but failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by four partner European Reference Networks, were taken forward for interpretation by clinical experts. This reanalysis has resulted in a molecular diagnosis being provided to 51 families in this sample, with ClinCNV performing the best of the three algorithms. We also identified partially explanatory pathogenic CNVs in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs.