Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Michael A. Levy; Haley McConkey; Jennifer Kerkhof; Mouna Barat-Houari; Sara Bargiacchi; Elisa Biamino; María Palomares Bralo; Gerarda Cappuccio; Andrea Ciolfi; Angus Clarke; Barbara R. DuPont; Mariet W. Elting; Laurence Faivre; Timothy Fee; Robin S. Fletcher; Florian Cherik; Aidin Foroutan; Michael J. Friez; Cristina Gervasini; Sadegheh Haghshenas; Benjamin A. Hilton; Zandra Jenkins; Simranpreet Kaur; Suzanne Lewis; Raymond J. Louie; Silvia Maitz; Donatella Milani; Angela T. Morgan; Renske Oegema; Elsebet Østergaard; Nathalie Ruiz Pallares; Maria Piccione; Simone Pizzi; Astrid S. Plomp; Cathryn Poulton; Jack Reilly; Raissa Relator; Rocio Rius; Stephen Robertson; Kathleen Rooney; Justine Rousseau; Gijs W.E. Santen; Fernando Santos-Simarro; Josephine Schijns; Gabriella Maria Squeo; Miya St John; Christel Thauvin-Robinet; Giovanna Traficante; Pleuntje J. van der Sluijs; Samantha A. Vergano; Niels Vos; Kellie K. Walden; Dimitar Azmanov; Tugce Balci; Siddharth Banka; Jozef Gecz; Peter Henneman; Jennifer A. Lee; Marcel M.A.M. Mannens; Tony Roscioli; Victoria Siu; David J. Amor; Gareth Baynam; Eric G. Bend; Kym Boycott; Nicola Brunetti-Pierri; Philippe M. Campeau; John Christodoulou; David Dyment; Natacha Esber; Jill A. Fahrner; Mark D. Fleming; David Genevieve; Kristin D. Kerrnohan; Alisdair McNeill; Leonie A. Menke; Giuseppe Merla; Paolo Prontera; Cheryl Rockman-Greenberg; Charles Schwartz; Steven A. Skinner; Roger E. Stevenson; Antonio Vitobello; Marco Tartaglia; Marielle Alders; Matthew L. Tedder; Bekim Sadikovic

doi:10.1016/j.xhgg.2021.100075

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Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

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Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Michael A. Levy, Haley McConkey, Jennifer Kerkhof, Mouna Barat-Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, …

HGG advances, Vol.3(1), pp.100075-100075

13/01/2022

DOI: https://doi.org/10.1016/j.xhgg.2021.100075

PMID: 35047860

Résumé

Clinical diagnostics

DNA methylation

Epigenetics

Episignatures

Neurodevelopmental disorders

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

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Titre: Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders
Créateurs - sans rôle: Michael A. Levy
Haley McConkey
Jennifer Kerkhof
Mouna Barat-Houari - Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France
Sara Bargiacchi - Medical Genetics Unit, "A. Meyer" Children's Hospital of Florence, Florence, Italy
Elisa Biamino - University of Turin
María Palomares Bralo - Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
Gerarda Cappuccio - Department of Translational Medicine, Federico II University of Naples, Naples, Italy
Andrea Ciolfi - Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
Angus Clarke - Cardiff University
Barbara R. DuPont - Greenwood Genetic Center
Mariet W. Elting - Vrije Universiteit Amsterdam
Laurence Faivre - INSERM-Université de Bourgogne UMR1231 GAD « Génétique Des Anomalies du Développement », FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France
Timothy Fee - Greenwood Genetic Center
Robin S. Fletcher - Greenwood Genetic Center
Florian Cherik - Genetic medical center, CHU Clermont Ferrand, France
Aidin Foroutan - Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
Michael J. Friez - Greenwood Genetic Center
Cristina Gervasini - Division of Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
Sadegheh Haghshenas - Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
Benjamin A. Hilton - Greenwood Genetic Center
Zandra Jenkins - University of Otago
Simranpreet Kaur - The University of Melbourne
Suzanne Lewis - University of British Columbia
Raymond J. Louie - Greenwood Genetic Center
Silvia Maitz - Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, Hospital San Gerardo, Monza, Italy
Donatella Milani - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Angela T. Morgan - The University of Melbourne
Renske Oegema - University Medical Center Utrecht
Elsebet Østergaard - Copenhagen University Hospital
Nathalie Ruiz Pallares - Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France
Maria Piccione - Medical Genetics Unit Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
Simone Pizzi - Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
Astrid S. Plomp - University of Amsterdam
Cathryn Poulton - Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia
Jack Reilly - Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
Raissa Relator
Rocio Rius - Murdoch Children's Research Institute
Stephen Robertson - University of Otago
Kathleen Rooney
Justine Rousseau - Centre Hospitalier Universitaire Sainte-Justine
Gijs W.E. Santen - Department of Clinical Genetics, LUMC, Leiden, the Netherlands
Fernando Santos-Simarro - Hospital Universitario La Paz
Josephine Schijns - University of Amsterdam
Gabriella Maria Squeo - University of Naples Federico II
Miya St John - Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia
Christel Thauvin-Robinet - INSERM-Université de Bourgogne UMR1231 GAD « Génétique Des Anomalies du Développement », FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France
Giovanna Traficante - Medical Genetics Unit, "A. Meyer" Children's Hospital of Florence, Florence, Italy
Pleuntje J. van der Sluijs - Department of Clinical Genetics, LUMC, Leiden, the Netherlands
Samantha A. Vergano - Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA
Niels Vos - University of Amsterdam
Kellie K. Walden - Greenwood Genetic Center
Dimitar Azmanov - Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Australia
Tugce Balci - Department of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A 3K7, Canada
Siddharth Banka - University of Manchester
Jozef Gecz - The University of Adelaide
Peter Henneman - University of Amsterdam
Jennifer A. Lee - Greenwood Genetic Center
Marcel M.A.M. Mannens - University of Amsterdam
Tony Roscioli - Neuroscience Research Australia
Victoria Siu - Department of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A 3K7, Canada
David J. Amor - The University of Melbourne
Gareth Baynam - Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia
Eric G. Bend - PreventionGenetics, Marshfield, WI, USA
Kym Boycott - University of Ottawa
Nicola Brunetti-Pierri - Department of Translational Medicine, Federico II University of Naples, Naples, Italy
Philippe M. Campeau - Centre Hospitalier Universitaire Sainte-Justine
John Christodoulou - The University of Melbourne
David Dyment - Children's Hospital of Eastern Ontario
Natacha Esber - KAT6A Foundation
Jill A. Fahrner - Johns Hopkins University
Mark D. Fleming - Boston Children's Hospital
David Genevieve - Inserm
Kristin D. Kerrnohan - Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Alisdair McNeill - University of Sheffield
Leonie A. Menke - University of Amsterdam
Giuseppe Merla - Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Paolo Prontera - University of Perugia
Cheryl Rockman-Greenberg - University of Manitoba
Charles Schwartz - Greenwood Genetic Center, Greenwood, SC 29646, USA
Steven A. Skinner - Greenwood Genetic Center
Roger E. Stevenson - Greenwood Genetic Center
Antonio Vitobello - Université de Bourgogne
Marco Tartaglia - Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
Marielle Alders - University of Amsterdam
Matthew L. Tedder - Greenwood Genetic Center
Bekim Sadikovic
Détails de publication: HGG advances, Vol.3(1), pp.100075-100075
Éditeur: Elsevier Inc
Identifiants: 99141194209311
Unité académique: Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Langue: English
Type de ressource: Journal article