Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders - Archive ouverte HAL Access content directly
Journal Articles European Journal of Human Genetics Year : 2024

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

Thomas Husson (1) , François Lecoquierre , Gaël Nicolas , Anne-Claire Richard , Alexandra Afenjar , Séverine Audebert-Bellanger , Catherine Badens (2) , Frédéric Bilan (3) , Varoona Bizaoui , Anne Boland (4) , Marie-Noëlle Bonnet-Dupeyron , Elise Brischoux-Boucher , Céline Bonnet (5) , Marie Bournez , Odile Boute , Perrine Brunelle (6) , Roseline Caumes , Perrine Charles , Nicolas Chassaing , Nicolas Chatron (7) , Benjamin Cogné (8) , Estelle Colin , Valérie Cormier-Daire (9) , Rodolphe Dard , Benjamin Dauriat , Julian Delanne (10) , Jean-François Deleuze , Florence Demurger , Anne-Sophie Denommé-Pichon , Christel Depienne , Anne Dieux , Christèle Dubourg (11, 12) , Patrick Edery (13) , Salima El Chehadeh (14, 15) , Laurence Faivre , Patricia Fergelot (16) , Mélanie Fradin (12) , Aurore Garde , David Geneviève (17) , Brigitte Gilbert-Dussardier , Cyril Goizet , Alice Goldenberg , Evan Gouy (18) , Anne-Marie Guerrot , Anne Guimier , Inès Harzalla , Delphine Héron , Bertrand Isidor , Didier Lacombe , Xavier Le Guillou Horn (19) , Boris Keren , Alma Kuechler , Elodie Lacaze , Alinoë Lavillaureix (11) , Daphné Lehalle , Gaëtan Lesca , James Lespinasse , Jonathan Levy , Stanislas Lyonnet , Godeliève Morel , Nolwenn Jean-Marçais (12) , Sandrine Marlin , Luisa Marsili , Cyril Mignot , Sophie Nambot , Mathilde Nizon , Robert Olaso , Laurent Pasquier (12) , Laurine Perrin , Florence Petit , Veronique Pingault , Amélie Piton , Fabienne Prieur , Audrey Putoux , Marc Planes , Sylvie Odent (12, 11) , Chloé Quélin (12) , Sylvia Quemener-Redon (20) , Mélanie Rama , Marlène Rio , Massimiliano Rossi , Elise Schaefer , Sophie Rondeau , Pascale Saugier-Veber , Thomas Smol , Sabine Sigaudy , Renaud Touraine , Frederic Tran Mau-Them , Aurélien Trimouille (16) , Julien van Gils , Clémence Vanlerberghe , Valérie Vantalon , Gabriella Vera , Marie Vincent , Alban Ziegler , Olivier Guillin , Dominique Campion , Camille Charbonnier (1)
1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
3 LNEC [Poitiers] - Laboratoire de neurosciences expérimentales et cliniques
4 CNRGH - Centre National de Recherche en Génomique Humaine
5 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
6 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
7 PGNM - Pathophysiologie et génétique du neurone et du muscle
8 Institut du Thorax [Nantes]
9 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
10 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
11 IGDR - Institut de Génétique et Développement de Rennes
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
13 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
14 IGMA - Institut de génétique médicale d’Alsace
15 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
16 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
17 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
18 MeLiS - Mécanismes en sciences intégratives du vivant
19 LMA [Poitiers] - Laboratoire de mathématiques et applications [UMR 7348]
20 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
François Lecoquierre
  • Function : Author
Gaël Nicolas
Anne-Claire Richard
  • Function : Author
Alexandra Afenjar
  • Function : Author
Séverine Audebert-Bellanger
  • Function : Author
Varoona Bizaoui
  • Function : Author
Marie-Noëlle Bonnet-Dupeyron
  • Function : Author
Elise Brischoux-Boucher
Marie Bournez
Odile Boute
  • Function : Author
Roseline Caumes
  • Function : Author
Perrine Charles
  • Function : Author
Nicolas Chassaing
Benjamin Cogné
Estelle Colin
  • Function : Author
Rodolphe Dard
  • Function : Author
Benjamin Dauriat
  • Function : Author
Jean-François Deleuze
  • Function : Author
Florence Demurger
  • Function : Author
Anne-Sophie Denommé-Pichon
Christel Depienne
Anne Dieux
  • Function : Author
Laurence Faivre
  • Function : Author
Aurore Garde
  • Function : Author
Brigitte Gilbert-Dussardier
Cyril Goizet
  • Function : Author
Alice Goldenberg
  • Function : Author
Anne-Marie Guerrot
  • Function : Author
Anne Guimier
  • Function : Author
Inès Harzalla
  • Function : Author
Delphine Héron
  • Function : Author
Bertrand Isidor
  • Function : Author
Didier Lacombe
  • Function : Author
Boris Keren
  • Function : Author
Alma Kuechler
  • Function : Author
Elodie Lacaze
  • Function : Author
Daphné Lehalle
  • Function : Author
Gaëtan Lesca
James Lespinasse
  • Function : Author
Jonathan Levy
Stanislas Lyonnet
  • Function : Author
Godeliève Morel
Sandrine Marlin
  • Function : Author
Luisa Marsili
Cyril Mignot
  • Function : Author
Sophie Nambot
Mathilde Nizon
Robert Olaso
  • Function : Author
Laurine Perrin
Florence Petit
  • Function : Author
Veronique Pingault
  • Function : Author
Amélie Piton
Fabienne Prieur
  • Function : Author
Audrey Putoux
  • Function : Author
Marc Planes
  • Function : Author
Mélanie Rama
  • Function : Author
Marlène Rio
Massimiliano Rossi
Elise Schaefer
  • Function : Author
Sophie Rondeau
  • Function : Author
Pascale Saugier-Veber
Thomas Smol
  • Function : Author
Sabine Sigaudy
  • Function : Author
Renaud Touraine
  • Function : Author
Frederic Tran Mau-Them
Julien van Gils
Clémence Vanlerberghe
  • Function : Author
Valérie Vantalon
  • Function : Author
Gabriella Vera
Marie Vincent
Alban Ziegler
  • Function : Author
Olivier Guillin
  • Function : Author
Dominique Campion
  • Function : Author

Abstract

Variants 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.

Domains

Genetics
Fichier principal
Vignette du fichier
s41431-023-01474-x.pdf (1.72 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

hal-04283066 , version 1 (15-11-2023)

Licence

Attribution

Identifiers

Cite

Thomas Husson, François Lecoquierre, Gaël Nicolas, Anne-Claire Richard, Alexandra Afenjar, et al.. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders. European Journal of Human Genetics, 2024, 32 (2), pp.190-199. ⟨10.1038/s41431-023-01474-x⟩. ⟨hal-04283066⟩
83 View
30 Download

Altmetric

Share

Gmail Facebook X LinkedIn More