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Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders.

dc.rights.licenseopenen_US
dc.contributor.authorHUSSON, Thomas
dc.contributor.authorLECOQUIERRE, François
dc.contributor.authorNICOLAS, Gaël
dc.contributor.authorRICHARD, Anne-Claire
dc.contributor.authorAFENJAR, Alexandra
dc.contributor.authorAUDEBERT-BELLANGER, Séverine
dc.contributor.authorBADENS, Catherine
dc.contributor.authorBILAN, Frédéric
dc.contributor.authorBIZAOUI, Varoona
dc.contributor.authorBOLAND, Anne
dc.contributor.authorBONNET-DUPEYRON, Marie-Noëlle
dc.contributor.authorBRISCHOUX-BOUCHER, Elise
dc.contributor.authorBONNET, Celine
dc.contributor.authorBOURNEZ, Marie
dc.contributor.authorBOUTE, Odile
dc.contributor.authorBRUNELLE, Perrine
dc.contributor.authorCAUMES, Roseline
dc.contributor.authorCHARLES, Perrine
dc.contributor.authorCHASSAING, Nicolas
dc.contributor.authorCHATRON, Nicolas
dc.contributor.authorCOGNÉ, Benjamin
dc.contributor.authorCOLIN, Estelle
dc.contributor.authorCORMIER-DAIRE, Valérie
dc.contributor.authorDARD, Rodolphe
dc.contributor.authorDAURIAT, Benjamin
dc.contributor.authorDELANNE, Julian
dc.contributor.authorDELEUZE, Jean-François
dc.contributor.authorDEMURGER, Florence
dc.contributor.authorDENOMMÉ-PICHON, Anne-Sophie
dc.contributor.authorDEPIENNE, Christel
dc.contributor.authorDIEUX, Anne
dc.contributor.authorDUBOURG, Christèle
dc.contributor.authorEDERY, Patrick
dc.contributor.authorEL CHEHADEH, Salima
dc.contributor.authorFAIVRE, Laurence
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorFERGELOT, Patricia
dc.contributor.authorFRADIN, Mélanie
dc.contributor.authorGARDE, Aurore
dc.contributor.authorGENEVIÈVE, David
dc.contributor.authorGILBERT-DUSSARDIER, Brigitte
hal.structure.identifierInstitut de Neurosciences cognitives et intégratives d'Aquitaine [INCIA]
dc.contributor.authorGOIZET, Cyril
dc.contributor.authorGOLDENBERG, Alice
dc.contributor.authorGOUY, Evan
dc.contributor.authorGUERROT, Anne-Marie
dc.contributor.authorGUIMIER, Anne
dc.contributor.authorHARZALLA, Inès
dc.contributor.authorHÉRON, Delphine
dc.contributor.authorISIDOR, Bertrand
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorLACOMBE, Didier
dc.contributor.authorLE GUILLOU HORN, Xavier
dc.contributor.authorKEREN, Boris
dc.contributor.authorKUECHLER, Alma
dc.contributor.authorLACAZE, Elodie
dc.contributor.authorLAVILLAUREIX, Alinoë
dc.contributor.authorLEHALLE, Daphné
dc.contributor.authorLESCA, Gaetan
dc.contributor.authorLESPINASSE, James
dc.contributor.authorLEVY, Jonathan
dc.contributor.authorLYONNET, Stanislas
dc.contributor.authorMOREL, Godeliève
dc.contributor.authorJEAN-MARÇAIS, Nolwenn
dc.contributor.authorMARLIN, Sandrine
dc.contributor.authorMARSILI, Luisa
dc.contributor.authorMIGNOT, Cyril
dc.contributor.authorNAMBOT, Sophie
dc.contributor.authorNIZON, Mathilde
dc.contributor.authorOLASO, Robert
dc.contributor.authorPASQUIER, Laurent
dc.contributor.authorPERRIN, Laurine
dc.contributor.authorPETIT, Florence
dc.contributor.authorPINGAULT, Veronique
dc.contributor.authorPITON, Amelie
dc.contributor.authorPRIEUR, Fabienne
dc.contributor.authorPUTOUX, Audrey
dc.contributor.authorPLANES, Marc
dc.contributor.authorODENT, Sylvie
dc.contributor.authorQUELIN, Chloe
dc.contributor.authorQUEMENER-REDON, Sylvia
dc.contributor.authorRAMA, Mélanie
dc.contributor.authorRIO, Marlène
dc.contributor.authorROSSI, Massimiliano
dc.contributor.authorSCHAEFER, Elise
dc.contributor.authorRONDEAU, Sophie
dc.contributor.authorSAUGIER-VEBER, Pascale
dc.contributor.authorSMOL, Thomas
dc.contributor.authorSIGAUDY, Sabine
dc.contributor.authorTOURAINE, Renaud
dc.contributor.authorMAU-THEM, Frederic Tran
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorTRIMOUILLE, Aurelien
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorVAN GILS, Julien
dc.contributor.authorVANLERBERGHE, Clémence
dc.contributor.authorVANTALON, Valérie
dc.contributor.authorVERA, Gabriella
dc.contributor.authorVINCENT, Marie
dc.contributor.authorZIEGLER, Alban
dc.contributor.authorGUILLIN, Olivier
dc.contributor.authorCAMPION, Dominique
dc.contributor.authorCHARBONNIER, Camille
dc.date.accessioned2023-11-28T15:42:08Z
dc.date.available2023-11-28T15:42:08Z
dc.date.issued2023-10-23
dc.identifier.issn1476-5438en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/186204
dc.description.abstractEnVariants 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.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.title.enEpisignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders.
dc.title.alternativeEur J Hum Geneten_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41431-023-01474-xen_US
dc.identifier.pubmed37872275en_US
bordeaux.journalEuropean Journal of Human Geneticsen_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.institutionCNRS
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
workflow.import.sourcepubmed
dc.rights.ccCC BYen_US
bordeaux.COinSctx_ver=Z39.88-2004&amp;rft_val_fmt=info:ofi/fmt:kev:mtx:journal&amp;rft.jtitle=European%20Journal%20of%20Human%20Genetics&amp;rft.date=2023-10-23&amp;rft.eissn=1476-5438&amp;rft.issn=1476-5438&amp;rft.au=HUSSON,%20Thomas&amp;LECOQUIERRE,%20Fran%C3%A7ois&amp;NICOLAS,%20Ga%C3%ABl&amp;RICHARD,%20Anne-Claire&amp;AFENJAR,%20Alexandra&amp;rft.genre=article


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