A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Anne-Sophie Denommé-Pichon, 1; Leslie Matalonga, 2; Elke de Boer, 3; Adam Jackson, 4; Elisa Benetti, 5; Siddharth Banka, 4; Ange-Line Bruel, 6; Andrea Ciolfi, 7; Jill Clayton-Smith, 4; Bruno Dallapiccola, 7; Yannis Duffourd, 6; Kornelia Ellwanger, 8; Chiara Fallerini, 9; Christian Gilissen 10,; Holm Graessner, 8; B Haack 8, Tobias; Marketa Havlovicova 11,; Alexander Hoischen 12,; Nolwenn Jean-Marçais 13,; Tjitske Kleefstra 14,; Estrella López-Martín 15,; Milan Macek 11,; Maria Antonietta Mencarelli 16,; Sébastien Moutton 17,; Rolph Pfundt, 3; Simone Pizzi, 7; Manuel Posada 15,; Francesca Clementina Radio, 7; Alessandra Renieri 18,; Caroline Rooryck 19,; Lukas Ryba 11,; Hana Safraou, 6; Martin Schwarz 11,; Marco Tartaglia, 7; Christel Thauvin-Robinet 20,; Julien Thevenon 17,; Frédéric Tran Mau-Them, 6; Aurélien Trimouille 21,; Pavel Votypka 11,; B A de Vries 3, Bert; H Willemsen 3, Marjolein; Birte Zurek, 8; Alain Verloes 22,; Christophe Philippe, 6; DITF-ITHACA, Solve-RD; Solve-RD SNV-indel Working Group,; Consortia, Solve-RD; Group, Orphanomix; Antonio Vitobello, 6; E L M Vissers 3, Lisenka; Laurence Faivre 23,; Balestrini, Simona; Guerrini, Renzo

doi:10.1016/j.gim.2023.100018

Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned.

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing / Anne-Sophie Denommé-Pichon 1, Leslie Matalonga 2, Elke de Boer 3, Adam Jackson 4, Elisa Benetti 5, Siddharth Banka 4, Ange-Line Bruel 6, Andrea Ciolfi 7, Jill Clayton-Smith 4, Bruno Dallapiccola 7, Yannis Duffourd 6, Kornelia Ellwanger 8, Chiara Fallerini 9, Christian Gilissen 10, Holm Graessner 8, Tobias B Haack 8, Marketa Havlovicova 11, Alexander Hoischen 12, Nolwenn Jean-Marçais 13, Tjitske Kleefstra 14, Estrella López-Martín 15, Milan Macek 11, Maria Antonietta Mencarelli 16, Sébastien Moutton 17, Rolph Pfundt 3, Simone Pizzi 7, Manuel Posada 15, Francesca Clementina Radio 7, Alessandra Renieri 18, Caroline Rooryck 19, Lukas Ryba 11, Hana Safraou 6, Martin Schwarz 11, Marco Tartaglia 7, Christel Thauvin-Robinet 20, Julien Thevenon 17, Frédéric Tran Mau-Them 6, Aurélien Trimouille 21, Pavel Votypka 11, Bert B A de Vries 3, Marjolein H Willemsen 3, Birte Zurek 8, Alain Verloes 22, Christophe Philippe 6; Solve-RD DITF-ITHACA; Solve-RD SNV-indel Working Group; Solve-RD Consortia; Orphanomix Group; Antonio Vitobello 6, Lisenka E L M Vissers 3, Laurence Faivre 23, Simona Balestrini, Renzo Guerrini. - In: GENETICS IN MEDICINE. - ISSN 1530-0366. - ELETTRONICO. - (2023), pp. 0-0. [10.1016/j.gim.2023.100018]