HGG Advances (Jan 2022)
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
Affiliations
- Michael A. Levy
- Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada
- Haley McConkey
- Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada
- Jennifer Kerkhof
- Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada
- 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
- Department of Pediatrics, University of Turin, Turin, Italy
- 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; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
- Andrea Ciolfi
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Angus Clarke
- Cardiff University School of Medicine, Cardiff, UK
- Barbara R. DuPont
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Mariet W. Elting
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Laurence Faivre
- INSERM-Université de Bourgogne UMR1231 GAD « Génétique Des Anomalies du Développement », FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France; Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
- Timothy Fee
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Robin S. Fletcher
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Florian Cherik
- Genetic medical center, CHU Clermont Ferrand, France; Montpellier University, Reference Center for Rare Disease, Medical Genetic Department for Rare Disease and Personalize Medicine, Inserm Unit 1183, CHU Montpellier, Montpellier, France
- Aidin Foroutan
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Michael J. Friez
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- 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, Greenwood, SC 29646, USA
- Zandra Jenkins
- Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Simranpreet Kaur
- Brain and Mitochondrial Research Group, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia
- Suzanne Lewis
- BC Children's and Women's Hospital and Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, Canada
- Raymond J. Louie
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Silvia Maitz
- Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, Hospital San Gerardo, Monza, Italy
- Donatella Milani
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Angela T. Morgan
- Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia
- Renske Oegema
- Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Elsebet Østergaard
- Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- 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
- Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- 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
- Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada
- Rocio Rius
- Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia
- Stephen Robertson
- Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Kathleen Rooney
- Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Justine Rousseau
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada
- Gijs W.E. Santen
- Department of Clinical Genetics, LUMC, Leiden, the Netherlands
- Fernando Santos-Simarro
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
- Josephine Schijns
- Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Gabriella Maria Squeo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
- 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; Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, France Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon Bourgogne, CHU Dijon Bourgogne, Dijon, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital D'Enfants, CHU Dijon Bourgogne, 21000 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; Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA
- Niels Vos
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, Amsterdam, the Netherlands
- Kellie K. Walden
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- 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; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute, London, ON N6A5W9, Canada
- Siddharth Banka
- Division of Evolution, Infection & Genomics, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
- Jozef Gecz
- 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 Henneman
- Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Jennifer A. Lee
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Marcel M.A.M. Mannens
- Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Tony Roscioli
- Neuroscience Research Australia (NeuRA), Sydney, Australia; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia
- Victoria Siu
- Department of Pediatrics, Division of Medical Genetics, Western University, London, ON N6A 3K7, Canada; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre and Children's Health Research Institute, London, ON N6A5W9, Canada
- David J. Amor
- Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia
- Gareth Baynam
- Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia; Undiagnosed Diseases Program, Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia; Division of Paediatrics and Telethon Kids Institute, Faculty of Health and Medical Sciences, Perth, Australia
- Eric G. Bend
- PreventionGenetics, Marshfield, WI, USA
- Kym Boycott
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
- Nicola Brunetti-Pierri
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
- Philippe M. Campeau
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada
- John Christodoulou
- Brain and Mitochondrial Research Group, Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, Australia
- David Dyment
- Children's Hospital of Eastern Ontario, Ottawa, Canada
- Natacha Esber
- KAT6A Foundation
- Jill A. Fahrner
- Departments of Genetic Medicine and Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA
- Mark D. Fleming
- Department of Pathology, Boston Children's Hospital, Boston, MA, USA
- David Genevieve
- Montpellier University, Reference Center for Rare Disease, Medical Genetic Department for Rare Disease and Personalize Medicine, Inserm Unit 1183, CHU Montpellier, Montpellier, France
- Kristin D. Kerrnohan
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada; Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada
- Alisdair McNeill
- Department of Neuroscience, University of Sheffield, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
- Leonie A. Menke
- Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Giuseppe Merla
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy
- Paolo Prontera
- Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Perugia, Italy
- Cheryl Rockman-Greenberg
- Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba and Program in Genetics and Metabolism, Shared Health MB, Winnipeg, MB, Canada
- Charles Schwartz
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Steven A. Skinner
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Roger E. Stevenson
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Antonio Vitobello
- INSERM-Université de Bourgogne UMR1231 GAD « Génétique Des Anomalies du Développement », FHU-TRANSLAD, UFR Des Sciences de Santé, Dijon, France; Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, France Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon Bourgogne, CHU Dijon Bourgogne, Dijon, France
- Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Marielle Alders
- Amsterdam UMC, University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
- Matthew L. Tedder
- Greenwood Genetic Center, Greenwood, SC 29646, USA
- Bekim Sadikovic
- Verspeeten Clinical Genome Centre; London Health Sciences Centre, London, ON N6A 5W9, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Corresponding author
- Journal volume & issue
-
Vol. 3,
no. 1
p. 100075
Abstract
Summary: 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.
