ArticleEuropean journal of human genetics : EJHG2024
Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders.
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20 citing papers in PubMed.
- Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.Molecular genetics & genomic medicine · 2026Review
- Population-scale detection of methylation outliers from long-read genome sequencing.medRxiv : the preprint server for health sciences · 2026Article
- Familial pneumothorax in twins with Tatton-Brown-Rahman DNMT3A overgrowth syndrome.European journal of human genetics : EJHG · 2026Article
- Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterisation of chromatinopathies.Genome medicine · 2026Article
- Analysis Methods for Diagnosing Rare Neurodevelopmental Diseases with Episignatures: A Systematic Review of the Literature.Biomedicines · 2025Review
- Epigenetic Mechanisms in Fabry Disease: A Thematic Analysis Linking Differential Methylation Profiles and Genetic Modifiers to Disease Phenotype.Current issues in molecular biology · 2025Review
- DNA methylation and machine learning: challenges and perspective toward enhanced clinical diagnostics.Clinical epigenetics · 2025Review
- DNA Methylation at a Single Locus of Human Genome Accurately Recapitulates Episignature of CREBBP-Related Rubinstein-Taybi Syndrome.International journal of molecular sciences · 2025Article
- Worth the Effort: Lessons for Discovery and Care From an Unusual Case of Gorlin Syndrome.American journal of medical genetics. Part A · 2025Article
- 5-mC DNA methylation in neurodevelopment: from molecular mechanisms to therapeutic implications.Molecular biology reports · 2025Review
- Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption.Nature genetics · 2025Article
- Navigating an Uninformative Genomic Test Result: A Practical Guide.Journal of paediatrics and child health · 2025Review
- Looking back at 2024 in the European Journal of Human Genetics.European journal of human genetics : EJHG · 2025Article
- DNA methylation biomarkers of intellectual/developmental disability across the lifespan.Journal of neurodevelopmental disorders · 2025Review
- Diagnostic utility of single-locus DNA methylation mark in Sotos syndrome developed by nanopore sequencing-based episignature.Clinical epigenetics · 2025Article
- Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders.Genome medicine · 2025Article
- Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool.Clinical epigenetics · 2024Article
- A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.European journal of human genetics : EJHG · 2024Article
- Using exomes better.European journal of human genetics : EJHG · 2024Article
- 2023 in the European Journal of Human Genetics.European journal of human genetics : EJHG · 2024Article
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Authors and funding
98 authors.
Thomas HussonUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Psychiatry, F-76000, Rouen, France.ORCID 0000-0002-4088-5021
François LecoquierreUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and reference center for developmental disorders, F-76000, Rouen, France.
Gaël NicolasUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and reference center for developmental disorders, F-76000, Rouen, France.ORCID 0000-0001-9391-7800
Anne-Claire RichardUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and reference center for developmental disorders, F-76000, Rouen, France.
Alexandra AfenjarAPHP. Sorbonne Université, Centre de Référence Malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, département de génétique et embryologie médicale, Hôpital Trousseau, F-75012, Paris, France.
Séverine Audebert-BellangerService de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.
Catherine BadensAix Marseille Univ, INSERM, MMG, Marseille, France; APHM, service de génétique, Marseille, France.
Frédéric BilanCHU de Poitiers, Service de Génétique Médicale and Université de Poitiers, INSERM U1084, LNEC, F- 86000, Poitiers, France.
Varoona BizaouiService de génétique et neurodéveloppement, Pôle de Santé Mentale Enfant et Adolescent, Centre Hospitalier de l'Estran, Pontorson, France.
Anne BolandUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
Marie-Noëlle Bonnet-DupeyronConsultations de Génétique, Centre Hospitalier de Valence, 26953, Valence, France.
Elise Brischoux-BoucherCentre de génétique humaine, CHU Besancon, Universite de Bourgogne Franche-Comte, Besancon, France.ORCID 0000-0002-4816-1431
Céline BonnetLaboratoire de génétique médicale, CHRU Nancy, Nancy, France.ORCID 0000-0002-6799-0438
Marie BournezCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.ORCID 0000-0001-9666-0350
Odile BouteCHU Lille, Clinique de génétique Guy Fontaine, F-59000, Lille, France.
Perrine BrunelleUniv. Lille, CHU Lille, ULR 7364 - RADEME - Institut de Génétique Médicale, F-59000, Lille, France.
Roseline CaumesCHU Lille, Clinique de génétique Guy Fontaine, F-59000, Lille, France.
Perrine CharlesDépartement de génétique clinique, centre de référence des déficiences intellectuelles de causes rares, GHU Pitié Salpêtrière, Paris, France.
Nicolas ChassaingService de Génétique Médicale, CHU Toulouse, Toulouse, France.ORCID 0000-0003-0538-0981
Nicolas ChatronService de Génétique, Hospices Civils de Lyon, Lyon, France.
Benjamin CognéNantes Université, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.ORCID 0000-0002-5503-6292
Estelle ColinService de Génétique Médicale, CHU Angers, Angers, France.
Valérie Cormier-DaireService de médecine génomique des maladies rares, hôpital Necker Enfants Malades, Paris, France.
Rodolphe DardGénétique médicale, CHI Poissy-Saint-Germain-en-Laye, 78300, Poissy, France.
Benjamin DauriatService de cytogénétique et génétique médicale, Hôpital Mère Enfant, CHU Limoges, Limoges, France.
Julian DelanneCentre de Génétique et Centre de référence « Déficiences intellectuelles de causes rares », FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.
Jean-François DeleuzeUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
Florence DemurgerService de génétique, CHBA, Vannes, France.
Anne-Sophie Denommé-PichonÉquipe GAD, INSERM UMR1231, Université de Bourgogne, Dijon, France.ORCID 0000-0002-8986-8222
Christel DepienneInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID 0000-0002-7212-9554
Anne DieuxCHU Lille, Clinique de génétique Guy Fontaine, F-59000, Lille, France.
Christèle DubourgService de Génétique Moléculaire et Génomique, CHU Pontchaillou, Rennes, France.ORCID 0000-0003-1345-4522
Patrick EderyService de Génétique, Hospices Civils de Lyon, Lyon, France.
Salima El ChehadehService de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.ORCID 0000-0003-1613-6570
Laurence FaivreCentre de Génétique et Centre de référence « Déficiences intellectuelles de causes rares », FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.
Patricia FergelotDepartment of Medical Genetics, University Hospital of Bordeaux and INSERM U1211, University of Bordeaux, Bordeaux, France.
Mélanie FradinService de Génétique Clinique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Rennes, Rennes, France.
Aurore GardeCentre de Génétique et Centre de référence « Déficiences intellectuelles de causes rares », FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.
David GenevièveUniversité Montpellier, Inserm U1183, Montpellier, France.ORCID 0000-0001-6928-6287
Brigitte Gilbert-DussardierCHU de Poitiers, Service de Génétique Médicale, F-86000, Poitiers, France.ORCID 0000-0001-7182-9914
Cyril GoizetNRGEN team, Univ. Bordeaux, CNRS, INCIA, UMR 5287, EPHE, F-33000, Bordeaux, France.
Alice GoldenbergUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and reference center for developmental disorders, F-76000, Rouen, France.
Evan GouyService de Génétique, Hospices Civils de Lyon, Lyon, France.
Anne-Marie GuerrotUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and reference center for developmental disorders, F-76000, Rouen, France.
Anne GuimierService de médecine génomique des maladies rares - GHU Necker- Enfants malades, Paris, France.
Inès HarzallaService de Génétique, CHU Hôpital Nord, Saint Etienne, France.
Delphine HéronAPHP.Sorbonne Université, Département de Génétique, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Bertrand IsidorNantes Université, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.
Didier LacombeDepartment of Medical Genetics, University Hospital of Bordeaux and INSERM U1211, University of Bordeaux, Bordeaux, France.
Xavier Le Guillou HornCHU de Poitiers, Service de Génétique Médicale, F - 86000, Poitiers, France.ORCID 0000-0001-9350-8177
Boris KerenDépartement de génétique médicale, Hôpital Pitié-Salpêtrière, AP-HP.Sorbonne Université, 75013, Paris, France.
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Elodie LacazeLe Havre Hospital, Department of Medical Genetics, F 76600, Le Havre, France.
Alinoë LavillaureixCHU Rennes, Service de Génétique Clinique, Centre de Référence Anomalies du développement, FHU GenOMedS, Univ Rennes, CNRS, INSERM, IGDR, UMR 6290, ERL U1305, Rennes, France.ORCID 0000-0002-3727-9530
Daphné LehalleAPHP.Sorbonne Université, Département de Génétique, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Gaëtan LescaService de Génétique, Hospices Civils de Lyon, Lyon, France.ORCID 0000-0001-7691-9492
James LespinasseUF de génétique médicale, Centre Hospitalier Métropole Savoie, BP 31135, 73011, Chambéry, France.
Jonathan LevyGenetics Department, AP-HP, Robert-Debré University Hospital, Paris, France.ORCID 0000-0002-8822-816X
Stanislas LyonnetService de médecine génomique des maladies rares, Hôpital Universitaire Necker-Enfants malades, APHP, Paris, France.
Godeliève MorelService de Génétique Clinique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Rennes, Rennes, France.ORCID 0000-0002-4132-6264
Nolwenn Jean-MarçaisCHU Rennes, Service de Génétique Clinique, Centre de Référence Anomalies du développement, FHU GenOMedS, Rennes, France.
Sandrine MarlinService de médecine génomique des maladies rares - GHU Necker- Enfants malades, Paris, France.
Luisa MarsiliCHU Lille, Clinique de génétique Guy Fontaine, F-59000, Lille, France.ORCID 0000-0002-6691-541X
Cyril MignotAPHP.Sorbonne Université, Département de Génétique, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Sophie NambotCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.ORCID 0000-0002-9630-5049
Mathilde NizonNantes Université, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.ORCID 0000-0003-2170-4210
Robert OlasoUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
Laurent PasquierCHU Rennes, Service de Génétique Clinique, Centre de Référence Anomalies du développement, FHU GenOMedS, Rennes, France.ORCID 0000-0003-3985-1286
Laurine PerrinMédecine Physique et Réadaptation pédiatrique CHU Saint-Etienne, 42055, Saint-Etienne Cedex 2, France.ORCID 0009-0004-3747-1743
Florence PetitCHU Lille, Clinique de génétique Guy Fontaine, F-59000, Lille, France.
Veronique PingaultService de Médecine Génomique des maladies rares, AP-HP. Centre, Hôpital Necker-Enfants Malades, F-75015, Paris, France.
Amélie PitonLaboratoire de diagnostic génétique, IGMA, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.ORCID 0000-0003-0408-7468
Fabienne PrieurService de Génétique, CHU Hôpital Nord, Saint Etienne, France.
Audrey PutouxService de Génétique, Hospices Civils de Lyon, Lyon, France.
Marc PlanesService de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.
Sylvie OdentCHU Rennes, Service de Génétique Clinique, Centre de Référence Anomalies du développement, FHU GenOMedS, Univ Rennes, CNRS, INSERM, IGDR, UMR 6290, ERL U1305, Rennes, France.
Chloé QuélinService de Génétique Clinique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Rennes, Rennes, France.
Sylvia Quemener-RedonService de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.
Mélanie RamaCHU Lille - Institut de Génétique Médicale, F-59000, Lille, France.
Marlène RioService de médecine génomique des maladies rares - GHU Necker- Enfants malades, Paris, France.ORCID 0000-0003-2049-5058
Massimiliano RossiService de Génétique, Hospices Civils de Lyon, Lyon, France.ORCID 0000-0002-5797-8152
Elise SchaeferService de Génétique Médicale -Institut de Génétique Médicale d'Alsace - CHU Strasbourg, Strasbourg, France.
Sophie RondeauService de médecine génomique des maladies rares - GHU Necker- Enfants malades, Paris, France.
Pascale Saugier-VeberUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and reference center for developmental disorders, F-76000, Rouen, France.ORCID 0000-0002-8045-6432
Thomas SmolUniv. Lille, CHU Lille, ULR 7364 - RADEME - Institut de Génétique Médicale, F-59000, Lille, France.
Sabine SigaudyAix Marseille Univ, INSERM, MMG, CRMR syndromes malformatifs et anomalies du développement, département de génétique, APHM Hopital Timone, Marseille, France.
Renaud TouraineService de Génétique, CHU Hôpital Nord, Saint Etienne, France.
Frederic Tran Mau-ThemÉquipe GAD, INSERM UMR1231, Université de Bourgogne, Dijon, France.ORCID 0000-0002-3795-9456
Aurélien TrimouilleService de Pathologie, CHU Bordeaux, Bordeaux, France.ORCID 0000-0002-3457-5684
Julien Van GilsDepartment of Medical Genetics, University Hospital of Bordeaux and INSERM U1211, University of Bordeaux, Bordeaux, France.ORCID 0000-0003-1497-9363
Clémence VanlerbergheCHU Lille, Clinique de génétique Guy Fontaine, F-59000, Lille, France.
Valérie VantalonCentre d'Excellence InovAND-Service de psychiatrie de l'enfant et de l'adolescent-CHU Robert Debré, Paris, France.
Gabriella VeraUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and reference center for developmental disorders, F-76000, Rouen, France.ORCID 0000-0001-8352-5563
Marie VincentNantes Université, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.ORCID 0000-0003-1010-5618
Alban ZieglerService de Génétique Médicale, CHU Angers, Angers, France.
Olivier GuillinUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Psychiatry, F-76000, Rouen, France.
Dominique CampionUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Psychiatry, F-76000, Rouen, France.
Camille CharbonnierUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Biostatistics, F-76000, Rouen, France. camille.le-clezio@chu-rouen.fr.ORCID 0000-0003-1172-0196
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
Neurodevelopmental DisordersPathology, MolecularBiomarkersDNA MethylationHumansBiomarkers
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