ArticleAmerican journal of human genetics2020
Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT06475651 (Characterization and Contribution of Genome-wide DNA Methylation), which is not on this map. Cited by 180 papers, 3 of them syntheses that pooled it.
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180citing papers in PubMed, 3 pooled it
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset
Who cites it
180 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Paediatric DNA methylation profile scores: a systematic review and open-source atlas.EBioMedicine · 2026Pooled it
- A Comprehensive Approach to the Diagnosis of Leigh Syndrome Spectrum.Diagnostics (Basel, Switzerland) · 2024Guideline
- A systematic review of neuroimaging epigenetic research: calling for an increased focus on development.Molecular psychiatry · 2023Pooled it
- Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.Molecular genetics & genomic medicine · 2026Review
- An episignature informed systematic analysis to ascertain the clinical significance and consequences of CHD8 missense variants.European journal of human genetics : EJHG · 2026Article
- Biallelic inactivating variants in the chromatin remodeler DMAP1 cause a syndromic neurodevelopmental disorder.The Journal of clinical investigation · 2026Article
- From chromatin dynamics to brain disease: Polycomb-Trithorax mechanisms in neurodevelopment.Trends in neurosciences · 2026Review
- De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity.Nature communications · 2026Article
- Systematic evaluation of long-read and short-read sequencing in neurological disorders diagnosis: a direct comparison study of 310 patients.NPJ genomic medicine · 2026Article
- Ensilication preserves high-molecular weight native DNA for clinical long-read sequencing.Genome biology · 2026Article
- Data-Driven Insights into Hyperkinetic Disorders in Neurodevelopmental Syndromes and Epileptic Encephalopathies.Movement disorders clinical practice · 2026Review
- Variants in the CxxC domain of the epigenetic regulator KDM2B support its role in developmental eye anomalies.European journal of human genetics : EJHG · 2026Article
- Chromatinopathies: clinically overlapping disorders, revealing novel variants and their DNA methylation signatures.Clinical epigenetics · 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
- Pathogenic variants in the cohesin loader subunit MAU2 underlie a distinct Cornelia de Lange Syndrome subtype.Nature communications · 2026Article
- Clinical,medRxiv : the preprint server for health sciences · 2026Article
- Missense substitutions in the BTB domain of ZBTB24 can lead to protein instability and cause ICF2 syndrome.Human molecular genetics · 2026Article
- DNA Methylation Episignature as a Novel Diagnostic Tool for Diamond-Blackfan Anemia Syndrome.American journal of hematology · 2026Article
- Evaluating DNA methylation episignatures as a first-tier diagnostic test in individuals with suspected genetic disorders.European journal of human genetics : EJHG · 2026Article
- Functional and Epigenomic Consequences ofInternational journal of molecular sciences · 2026Article
120 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
69 authors.
Erfan Aref-EshghiMolecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada.
Jennifer KerkhofMolecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada.
Victor P PedroSchulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A5C1, Canada.
Groupe DI FranceGroupe DI, French Rare Disease Network filière AnDDI-Rare France.
Mouna Barat-HouariAutoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France.
Nathalie Ruiz-PallaresAutoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France.
Jean-Christophe AndrauInstitut de Génétique Moléculaire de Montpellier (IGMM), University Montpellier, CNRS-UMR5535, 34090 Montpellier, France.
Didier LacombeMedical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France.
Julien Van-GilsMedical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France.
Patricia FergelotMedical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France.
Christèle DubourgService de Génétique Moléculaire et Génomique, Centre Hospitalier Universitaire de Rennes, 35000 Rennes, France.
Valerie Cormier-DaireDepartment of Medical Genetics, Paris Descartes University, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital, 75015 Paris, France.
Sophie RondeauDepartment of Medical Genetics, Paris Descartes University, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital, 75015 Paris, France.
François LecoquierreNormandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F 76000, Normandy Center for Genomic and Personalized Medicine, 76183 Rouen, France.
Pascale Saugier-VeberNormandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F 76000, Normandy Center for Genomic and Personalized Medicine, 76183 Rouen, France.
Gaël NicolasNormandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F 76000, Normandy Center for Genomic and Personalized Medicine, 76183 Rouen, France.
Gaetan LescaDepartment of Medical Genetics, University Hospital of Lyon, 69007 Lyon, France.
Nicolas ChatronDepartment of Medical Genetics, University Hospital of Lyon, 69007 Lyon, France.
Damien SanlavilleDepartment of Medical Genetics, University Hospital of Lyon, 69007 Lyon, France.
Antonio VitobelloInserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, 15 boulevard du Maréchal de Lattre de Tassigny, 21000, Dijon Cedex, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, Dijon University Hospital, 21000 Dijon, France.
Laurence FaivreInserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, 15 boulevard du Maréchal de Lattre de Tassigny, 21000, Dijon Cedex, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, CHU Dijon, 21000, Dijon, France.
Christel Thauvin-RobinetInserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, 15 boulevard du Maréchal de Lattre de Tassigny, 21000, Dijon Cedex, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, CHU Dijon, 21000, Dijon, France.
Frederic LaumonnierUMR 1253, iBrain, Universite de Tours, Inserm, 37200 Tours, France; Centre Hospitalier Universitaire de Tours, Service de Genetique, 37000 Tours, France.
Martine RaynaudUMR 1253, iBrain, Universite de Tours, Inserm, 37200 Tours, France; Centre Hospitalier Universitaire de Tours, Service de Genetique, 37000 Tours, France.
Mariëlle AldersAmsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Marcel MannensAmsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Peter HennemanAmsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Raoul C HennekamDepartment of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, 1012 WX, the Netherlands.
Guillaume VelascoUniversité de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.
Claire FrancastelUniversité de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.
Damien UlvelingUniversité de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.
Andrea CiolfiGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy.
Simone PizziGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy.
Marco TartagliaGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy.
Solveig HeideDepartment of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.
Delphine HéronDepartment of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.
Cyril MignotDepartment of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.
Boris KerenDepartment of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.
Sandra WhalenUnit of Genetics, APHP Sorbonne University, Trousseau Hospital, 75012 Paris, France.
Alexandra AfenjarUnit of Genetics, APHP Sorbonne University, Trousseau Hospital, 75012 Paris, France.
Thierry BienvenuDepartment of Molecular Genetics, Cochin Hospital, 75014 Paris, France.
Philippe M CampeauDepartment of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada.
Justine RousseauDepartment of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada.
Michael A LevyMolecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A3K7, Canada.
Lauren BrickGenetic Division, Department of Pediatrics, McMaster University, Hamilton, ON L8S4K1, Canada.
Mariya KozenkoGenetic Division, Department of Pediatrics, McMaster University, Hamilton, ON L8S4K1, Canada.
Tugce B BalciDepartment of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A 3K7; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON N6A5W9, Canada.
Victoria Mok SiuDepartment of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A 3K7; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON N6A5W9, Canada.
Alan StuartMolecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada.
Mike KadourDepartment of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A5W9 Canada; St. Joseph's Health Care London, London, ON N6A5W9 Canada.
Jennifer MastersDepartment of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A5W9 Canada; St. Joseph's Health Care London, London, ON N6A5W9 Canada.
Kyoko TakanoCenter for Medical Genetics, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan.
Tjitske KleefstraDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Donders Center for Medical Neuroscience, 6525 GA Nijmegen, the Netherlands.
Nicole de LeeuwDepartment of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Donders Center for Medical Neuroscience, 6525 GA Nijmegen, the Netherlands.
Michael FieldGenetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
Marie ShawSchool of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.
Jozef GeczSchool of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5005, Australia.
Peter J AinsworthMolecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A3K7, Canada.
Hanxin LinMolecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A3K7, Canada.
David I RodenhiserChildren's Health Research Institute, London, ON N6A3K7, Canada; Department of Biochemistry, Western University, London, ON N6A3K7, Canada.
Michael J FriezGreenwood Genetic Center, Greenwood, SC 29646, USA.
Matt TedderGreenwood Genetic Center, Greenwood, SC 29646, USA.
Jennifer A LeeGreenwood Genetic Center, Greenwood, SC 29646, USA.
Barbara R DuPontGreenwood Genetic Center, Greenwood, SC 29646, USA.
Roger E StevensonGreenwood Genetic Center, Greenwood, SC 29646, USA.
Steven A SkinnerGreenwood Genetic Center, Greenwood, SC 29646, USA.
Charles E SchwartzGreenwood Genetic Center, Greenwood, SC 29646, USA.
David GenevieveMedical Genetic Department for Rare Diseases and Personalized Medicine, Reference Center AD SOOR, AnDDI-RARE, Groupe DI, Inserm U1183-Institute for Regenerative Medicine and Biotherapy, Montpellier University, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France.
Bekim SadikovicMolecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A3K7, Canada. Electronic address: Bekim.Sadikovic@lhsc.on.ca.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.
Indexed as
DNA MethylationPhenotypeCohort StudiesGenetic HeterogeneityHumansNeurodevelopmental DisordersSyndromeDNA methylationEpiSignepisignaturemolecular diagnosticsuncertain clinical casesVUS classification
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NCT06475651ClinicalTrials.gov
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