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Lookup NU author(s): Dr Ana TopfORCiD, Dr Karin Engelhardt, Professor Sophie Hambleton, Professor Jordi Diaz ManeraORCiD, Professor Chiara Marini Bettolo, Professor Volker StraubORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 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.
Author(s): Demidov G, Yaldiz B, Garcia-Pelaez J, de Boer E, Schuermans N, Paramonov I, Johansson LF, Musacchia F, Benetti E, Bullich G, Sablauskas K, Beltran S, Gilissen C, Hoischen A, Ossowski S, de Voer R, Lohmann K, Oliveira C, Topf A, Mignot C, Heron D, Drunat S, Verloes A, Moore R, Metcalfe A, Kohler S, Zonneveld-Huijssoon E, Kerstjens Frederikse WS, Abbott KM, van Gijn M, Ruvolo D, Roelofs-Prins D, Neerincx PB, van der Vries G, van der Velde JK, Swertz MA, Carneiro F, Ferreira P, Garrido L, Fernandes S, Gullo I, Ferreira M, Jose CS, Barbosa-Matos R, Peters S, Sommer AK, Spier I, Aretz S, Neri M, Bigoni S, Gualandi F, Selvatici R, Ferlini A, Piluso G, Zanobio M, Zeuli R, Torella A, Banfi S, Pinelli M, Morleo M, Nigro V, Smal N, Millevert C, Stamberger H, Weckhuysen S, De Ridder W, Van de Vondel L, Van de Vondel L, de Jonghe P, De Winter J, de Vries G, Baets J, Timmerman V, Muller J, Pini V, Perry L, Sarkozy A, Zaharieva I, Muntoni F, Rohrer J, Moloney P, Bellampalli R, Sisodiya SM, Magrinelli F, Cali E, Morsy H, Efthymiou S, Vandrovcova J, Reilly M, Houlden H, Hanna M, Costa A, Robert G, Danis D, Robinson P, Spalding D, Thomas C, Freeberg M, Keane T, Parkinson H, Krebsova A, Dolezalova P, Liskova P, Ryba L, Havlovicova M, Frankova V, Kremlikova RP, Thomasova D, Turnovec M, Macek M, Stojkovic T, Atalaia A, Cohen E, Eymard B, Metay C, Ben Yaou R, Nelson I, Allamand V, Evangelista T, Bonne G, Coarelli G, Heinzmann A, Guillot-Noel L, Davoine C-S, Durr A, Stevanin G, Lebreton E, Lucano C, Chahdil M, Hongnat O, Lagorce D, Hanauer M, Rath A, Bros-Facer V, Gumus G, Raineri E, Gut M, Dabad M, Codina AE, Pico D, Hernandez C, Fernandez-Callejo M, Corvo A, Papakonstantinou A, Matalonga L, Piscia D, Gut IG, Couturier V, Bruel A-L, Duffourd Y, Denomme-Pichon A-S, Vitobello A, Thauvin C, Faivre L, Jackson A, Alexander E, Banka S, Clayton-Smith J, Engelhardt K, Hambleton S, Manera JD, Bettolo CM, Straub V, et al
Publication type: Article
Publication status: Published
Journal: npj Genomic Medicine
Year: 2024
Volume: 9
Issue: 1
Online publication date: 26/10/2024
Acceptance date: 25/09/2024
Date deposited: 12/11/2024
ISSN (electronic): 2056-7944
Publisher: Nature Research
URL: https://doi.org/10.1038/s41525-024-00436-6
DOI: 10.1038/s41525-024-00436-6
Data Access Statement: All raw and processed data files are deposited at the EGA (Datasets EGAD00001009767, EGAD00001009768, EGAD00001009769, and EGAD00001009770, under Solve-RD study EGAS00001003851) and can be made available upon approval by the Data Access Committee (EGAC00001001319). The family (FAM) and participant (P) identifiers used in this manuscript are pseudonymized and known only to the researchers involved In Solve-RD. Code availability All the software tools used in this paper are open-source and freely available online at https://github.com/imgag/ClinCNV (ClinCNV 1.16.6), https://github.com/vplagnol/ExomeDepth (ExomeDepth 1.1.15), https://conifer.sourceforge.net/ (CoNIFER 0.2.2), https://github.com/lgmgeo/AnnotSV (AnnotSV v.3.0.7). Genome-Phenome Analysis Platform used for the metadata collection is available on https://platform.rd-connect.eu/.
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