International Journal of Molecular Sciences (Feb 2022)
Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for <i>KMT2A</i>-Related Syndrome
- Aidin Foroutan,
- Sadegheh Haghshenas,
- Pratibha Bhai,
- Michael A. Levy,
- Jennifer Kerkhof,
- Haley McConkey,
- Marcello Niceta,
- Andrea Ciolfi,
- Lucia Pedace,
- Evelina Miele,
- David Genevieve,
- Solveig Heide,
- Mariëlle Alders,
- Giuseppe Zampino,
- Giuseppe Merla,
- Mélanie Fradin,
- Eric Bieth,
- Dominique Bonneau,
- Klaus Dieterich,
- Patricia Fergelot,
- Elise Schaefer,
- Laurence Faivre,
- Antonio Vitobello,
- Silvia Maitz,
- Rita Fischetto,
- Cristina Gervasini,
- Maria Piccione,
- Ingrid van de Laar,
- Marco Tartaglia,
- Bekim Sadikovic,
- Anne-Sophie Lebre
Affiliations
- Aidin Foroutan
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Sadegheh Haghshenas
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Pratibha Bhai
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
- Michael A. Levy
- 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
- Haley McConkey
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
- Marcello Niceta
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Andrea Ciolfi
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Lucia Pedace
- Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Evelina Miele
- Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- David Genevieve
- 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
- Solveig Heide
- Department of Genetics, Referral Center for Intellectual Disabilities, APHP Sorbonne University, Pitié Salpêtrière Hospital, 75013 Paris, France
- Mariëlle Alders
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Giuseppe Zampino
- Center for Rare Diseases and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
- Giuseppe Merla
- Department of Molecular Medicine and Medical Biotechnology, Università di Napoli “Federico II”, 80131 Naples, Italy
- Mélanie Fradin
- Service de Génétique, CHU de Rennes, 35203 Rennes, France
- Eric Bieth
- Medical Genetics Department, University of Angers, CHU Angers, 49000 Angers, France
- Dominique Bonneau
- Department of genetics, CHU d’Angers, 49000 Angers, France and MitoVasc, UMR CNRS 6015-INSERM 1083, University of Angers, 49055 Angers, France
- Klaus Dieterich
- CHU Grenoble Alpes, Inserm, U1209, Institute of Advanced Biosciences, Université Grenoble Alpes, 38000 Grenoble, France
- Patricia Fergelot
- Medical Genetics Department, Inserm U1211, Reference Center AD SOOR, AnDDI-RARE, Bordeaux University, Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France
- Elise Schaefer
- Service de Génétique Médicale—Institut de Génétique Médicale d’Alsace—Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France
- Laurence Faivre
- Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, 15 boulevard du Maréchal de Lattre de Tassigny, 21000 Dijon, France
- Antonio Vitobello
- Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, 15 boulevard du Maréchal de Lattre de Tassigny, 21000 Dijon, France
- Silvia Maitz
- Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, 20900 Monza, Italy
- Rita Fischetto
- Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children’s Hospital, 02115 Bari, Italy
- Cristina Gervasini
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy
- Maria Piccione
- Department of Sciences for Health Promotion and Mother and Child Care “G. D’Alessandro”, University of Palermo, 90127 Palermo, Italy
- Ingrid van de Laar
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
- Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Anne-Sophie Lebre
- Team Physiopathologie des Maladies Psychiatriques, GDR3557-Institut de Psychiatrie, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Université de Paris, 75006 Paris, France
- DOI
- https://doi.org/10.3390/ijms23031815
- Journal volume & issue
-
Vol. 23,
no. 3
p. 1815
Abstract
Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
Keywords
- epigenetics
- DNA methylation
- episignature
- Wiedemann–Steiner syndrome
- <i>KMT2A</i> gene
- intellectual disability