Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders
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Published:2023-10-23
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ISSN:1018-4813
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Container-title:European Journal of Human Genetics
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language:en
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Short-container-title:Eur J Hum Genet
Author:
Husson ThomasORCID, Lecoquierre François, Nicolas GaëlORCID, Richard Anne-Claire, Afenjar Alexandra, Audebert-Bellanger Séverine, Badens Catherine, Bilan Frédéric, Bizaoui Varoona, Boland Anne, Bonnet-Dupeyron Marie-Noëlle, Brischoux-Boucher EliseORCID, Bonnet CélineORCID, Bournez MarieORCID, Boute Odile, Brunelle Perrine, Caumes Roseline, Charles Perrine, Chassaing NicolasORCID, Chatron Nicolas, Cogné BenjaminORCID, Colin Estelle, Cormier-Daire Valérie, Dard Rodolphe, Dauriat Benjamin, Delanne Julian, Deleuze Jean-François, Demurger Florence, Denommé-Pichon Anne-SophieORCID, Depienne ChristelORCID, Dieux Anne, Dubourg ChristèleORCID, Edery Patrick, El Chehadeh SalimaORCID, Faivre Laurence, Fergelot Patricia, Fradin Mélanie, Garde Aurore, Geneviève DavidORCID, Gilbert-Dussardier BrigitteORCID, Goizet Cyril, Goldenberg Alice, Gouy Evan, Guerrot Anne-Marie, Guimier Anne, Harzalla Inès, Héron Delphine, Isidor Bertrand, Lacombe Didier, Le Guillou Horn XavierORCID, Keren Boris, Kuechler Alma, Lacaze Elodie, Lavillaureix AlinoëORCID, Lehalle Daphné, Lesca GaëtanORCID, Lespinasse James, Levy JonathanORCID, Lyonnet Stanislas, Morel GodelièveORCID, Jean-Marçais Nolwenn, Marlin Sandrine, Marsili LuisaORCID, Mignot Cyril, Nambot SophieORCID, Nizon MathildeORCID, Olaso Robert, Pasquier LaurentORCID, Perrin LaurineORCID, Petit Florence, Pingault Veronique, Piton AmélieORCID, Prieur Fabienne, Putoux Audrey, Planes Marc, Odent Sylvie, Quélin Chloé, Quemener-Redon Sylvia, Rama Mélanie, Rio MarlèneORCID, Rossi MassimilianoORCID, Schaefer Elise, Rondeau Sophie, Saugier-Veber PascaleORCID, Smol Thomas, Sigaudy Sabine, Touraine Renaud, Mau-Them Frederic TranORCID, Trimouille AurélienORCID, Van Gils JulienORCID, Vanlerberghe Clémence, Vantalon Valérie, Vera GabriellaORCID, Vincent MarieORCID, Ziegler Alban, Guillin Olivier, Campion Dominique, Charbonnier CamilleORCID
Abstract
AbstractVariants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.
Funder
Fondation de l'Avenir pour la Recherche Médicale Appliquée Fondation Pierre Deniker pour la Recherche et la Prévention en Santé Mentale Cerveau progrès
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
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