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oai:repisalud.isciii.es:20.500.12105/156292025-05-09T09:17:16Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Denommé-Pichon, Anne-Sophie author Matalonga, Leslie author de Boer, Elke author Jackson, Adam author Benetti, Elisa author Banka, Siddharth author Bruel, Ange-Line author Ciolfi, Andrea author Clayton-Smith, Jill author Dallapiccola, Bruno author Duffourd, Yannis author Ellwanger, Kornelia author Fallerini, Chiara author Gilissen, Christian author Graessner, Holm author Haack, Tobias B author Havlovicova, Marketa author Hoischen, Alexander author Jean-Marçais, Nolwenn author Kleefstra, Tjitske author Lopez-Martin, Estrella author Macek, Milan author Mencarelli, Maria Antonietta author Moutton, Sébastien author Pfundt, Rolph author Pizzi, Simone author Posada De la Paz, Manuel author Radio, Francesca Clementina author Renieri, Alessandra author Rooryck, Caroline author Ryba, Lukas author Safraou, Hana author Schwarz, Martin author Tartaglia, Marco author Thauvin-Robinet, Christel author Thevenon, Julien author Tran Mau-Them, Frederic author Trimouille, Aurélien author Votypka, Pavel author de Vries, Bert B A author Willemsen, Marjolein H author Zurek, Birte author Verloes, Alain author Philippe, Christophe author Vitobello, Antonio author Vissers, Lisenka E L M author Faivre, Laurence author 2023-01-20 Purpose: 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. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. Genet Med. 2023 Apr;25(4):100018. http://hdl.handle.net/20.500.12105/15629 36681873 10.1016/j.gim.2023.100018 1530-0366 Genetics in medicine : official journal of the American College of Medical Genetics ClinVar Developmental disorder Exome reanalysis Rare diseases A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing