Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Cohort Studies DNA Methylation Genetic Heterogeneity Humans Neurodevelopmental Disorders / genetics Phenotype Syndrome
DNA methylation EpiSign VUS classification episignature molecular diagnostics uncertain clinical cases

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
05 03 2020
Historique:
received: 08 11 2019
accepted: 27 01 2020
pubmed: 29 2 2020
medline: 6 5 2020
entrez: 29 2 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ajhg.2020.01.019 PMID: 32109418 PMC: PMC7058829
pubmed: 32109418
pii: S0002-9297(20)30019-7
doi: 10.1016/j.ajhg.2020.01.019
pmc: PMC7058829
pii:
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

356-370

Commentaires et corrections

Type : ErratumIn

Informations de copyright

Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Auteurs

Erfan Aref-Eshghi (E)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada.

Jennifer Kerkhof (J)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada.

Victor P Pedro (VP)

Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A5C1, Canada.
Groupe DI, French Rare Disease Network filière AnDDI-Rare France.

Mouna Barat-Houari (M)

Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France.

Nathalie Ruiz-Pallares (N)

Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France.

Jean-Christophe Andrau (JC)

Institut de Génétique Moléculaire de Montpellier (IGMM), University Montpellier, CNRS-UMR5535, 34090 Montpellier, France.

Didier Lacombe (D)

Medical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France.

Julien Van-Gils (J)

Medical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France.

Patricia Fergelot (P)

Medical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France.

Christèle Dubourg (C)

Service de Génétique Moléculaire et Génomique, Centre Hospitalier Universitaire de Rennes, 35000 Rennes, France.

Valerie Cormier-Daire (V)

Department of Medical Genetics, Paris Descartes University, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital, 75015 Paris, France.

Sophie Rondeau (S)

Department of Medical Genetics, Paris Descartes University, INSERM UMR 1163, Imagine Institute, Necker Enfants Malades Hospital, 75015 Paris, France.

François Lecoquierre (F)

Normandie 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-Veber (P)

Normandie 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 Nicolas (G)

Normandie 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 Lesca (G)

Department of Medical Genetics, University Hospital of Lyon, 69007 Lyon, France.

Nicolas Chatron (N)

Department of Medical Genetics, University Hospital of Lyon, 69007 Lyon, France.

Damien Sanlaville (D)

Department of Medical Genetics, University Hospital of Lyon, 69007 Lyon, France.

Antonio Vitobello (A)

Inserm, 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 Faivre (L)

Inserm, 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-Robinet (C)

Inserm, 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 Laumonnier (F)

UMR 1253, iBrain, Universite de Tours, Inserm, 37200 Tours, France; Centre Hospitalier Universitaire de Tours, Service de Genetique, 37000 Tours, France.

Martine Raynaud (M)

UMR 1253, iBrain, Universite de Tours, Inserm, 37200 Tours, France; Centre Hospitalier Universitaire de Tours, Service de Genetique, 37000 Tours, France.

Mariëlle Alders (M)

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Marcel Mannens (M)

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Peter Henneman (P)

Amsterdam 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 Hennekam (RC)

Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, 1012 WX, the Netherlands.

Guillaume Velasco (G)

Université de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.

Claire Francastel (C)

Université de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.

Damien Ulveling (D)

Université de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.

Andrea Ciolfi (A)

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy.

Simone Pizzi (S)

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy.

Marco Tartaglia (M)

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy.

Solveig Heide (S)

Department of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.

Delphine Héron (D)

Department of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.

Cyril Mignot (C)

Department of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.

Boris Keren (B)

Department of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France.

Sandra Whalen (S)

Unit of Genetics, APHP Sorbonne University, Trousseau Hospital, 75012 Paris, France.

Alexandra Afenjar (A)

Unit of Genetics, APHP Sorbonne University, Trousseau Hospital, 75012 Paris, France.

Thierry Bienvenu (T)

Department of Molecular Genetics, Cochin Hospital, 75014 Paris, France.

Philippe M Campeau (PM)

Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada.

Justine Rousseau (J)

Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada.

Michael A Levy (MA)

Molecular 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 Brick (L)

Genetic Division, Department of Pediatrics, McMaster University, Hamilton, ON L8S4K1, Canada.

Mariya Kozenko (M)

Genetic Division, Department of Pediatrics, McMaster University, Hamilton, ON L8S4K1, Canada.

Tugce B Balci (TB)

Department 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 Siu (VM)

Department 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 Stuart (A)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada.

Mike Kadour (M)

Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A5W9 Canada; St. Joseph's Health Care London, London, ON N6A5W9 Canada.

Jennifer Masters (J)

Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A5W9 Canada; St. Joseph's Health Care London, London, ON N6A5W9 Canada.

Kyoko Takano (K)

Center for Medical Genetics, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan.

Tjitske Kleefstra (T)

Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Donders Center for Medical Neuroscience, 6525 GA Nijmegen, the Netherlands.

Nicole de Leeuw (N)

Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Donders Center for Medical Neuroscience, 6525 GA Nijmegen, the Netherlands.

Michael Field (M)

Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.

Marie Shaw (M)

School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.

Jozef Gecz (J)

School 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 Ainsworth (PJ)

Molecular 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 Lin (H)

Molecular 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 Rodenhiser (DI)

Children's Health Research Institute, London, ON N6A3K7, Canada; Department of Biochemistry, Western University, London, ON N6A3K7, Canada.

Michael J Friez (MJ)

Greenwood Genetic Center, Greenwood, SC 29646, USA.

Matt Tedder (M)

Greenwood Genetic Center, Greenwood, SC 29646, USA.

Jennifer A Lee (JA)

Greenwood Genetic Center, Greenwood, SC 29646, USA.

Barbara R DuPont (BR)

Greenwood Genetic Center, Greenwood, SC 29646, USA.

Roger E Stevenson (RE)

Greenwood Genetic Center, Greenwood, SC 29646, USA.

Steven A Skinner (SA)

Greenwood Genetic Center, Greenwood, SC 29646, USA.

Charles E Schwartz (CE)

Greenwood Genetic Center, Greenwood, SC 29646, USA.

David Genevieve (D)

Medical 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 Sadikovic (B)

Molecular 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.

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Classifications MeSH

questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Evaluation of DNA Methylation Episignatures...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Evaluation of DNA Methylation Episignatures...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Hétérogénéité génétique › Evaluation of DNA Methylation Episignatures...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Evaluation of DNA Methylation Episignatures...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Evaluation of DNA Methylation Episignatures...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Evaluation of DNA Methylation Episignatures...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Maladie › Syndrome › Evaluation of DNA Methylation Episignatures...