Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis
Clinical Epigenetics, vol. 16, pp. 99
Abstract
BACKGROUND: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. METHODS: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. RESULTS: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. CONCLUSIONS: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.
Authors 32
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Deborah Mackay corresponding
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, UK. djgm@soton.ac.uk
University of Southampton (University Road, Southampton SO17 1BJ - Royaume-Uni)
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Princess Anne Hospital · University Hospital Southampton NHS Foundation Trust · University of Southampton
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, UK
Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Trust, Southampton, UK
PAH - Princess Anne Hospital [Southampton, UK] (Southampton, UK - Royaume-Uni)
University Hospital Southampton NHS Foundation Trust (University Hospital Southampton NHS Foundation Trust Tremona Road Southampton Hampshire SO16 6YD - Royaume-Uni)
University of Southampton (University Road, Southampton SO17 1BJ - Royaume-Uni)
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University of East Anglia · Norwich Research Park
Affiliation as printed
Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, UK
UEA - University of East Anglia [Norwich] (Norwich Research Park, Norwich, NR4 7TJ, UK - Royaume-Uni)
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Inserm · Sorbonne Université · Hôpital Armand-Trousseau · Assistance Publique – Hôpitaux de Paris · Centre de Recherche Saint-Antoine
Affiliation as printed
Centre de Recherche Saint Antoine, Endocrinologie Moléculaire et Pathologies d'empreinte, INSERMSorbonne Université, Hôpital Armand TrousseauAPHP, 75012, Paris, France
CHU Trousseau [APHP] (26 Avenue du Dr Arnold Netter, 75012 Paris - France)
CRSA - Centre de Recherche Saint-Antoine (Bâtiment Kourilsky 34 rue Crozatier 75012 PARIS Sorbonne Université 27 rue Chaligny 75012 PARIS - France)
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Inserm · Sorbonne Université · Hôpital Armand-Trousseau · Assistance Publique – Hôpitaux de Paris · Centre de Recherche Saint-Antoine
Affiliation as printed
Centre de Recherche Saint Antoine, Endocrinologie Moléculaire et Pathologies d'empreinte, INSERMSorbonne Université, Hôpital Armand TrousseauAPHP, 75012, Paris, France
CHU Trousseau [APHP] (26 Avenue du Dr Arnold Netter, 75012 Paris - France)
CRSA - Centre de Recherche Saint-Antoine (Bâtiment Kourilsky 34 rue Crozatier 75012 PARIS Sorbonne Université 27 rue Chaligny 75012 PARIS - France)
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam UMC - Amsterdam University Medical Centers (1105 AZ Amsterdam - Pays-Bas)
UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam (Spui 21 1012 WX Amsterdam - Pays-Bas)
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
Departments of Pediatrics and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
Division of Human Genetics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
CHOP - Children’s Hospital of Philadelphia (3401 Civic Center Blvd, Philadelphia, PA 19104 - États-Unis)
Perelman School of Medicine (Philadelphia - États-Unis)
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam UMC - Amsterdam University Medical Centers (1105 AZ Amsterdam - Pays-Bas)
UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam (Spui 21 1012 WX Amsterdam - Pays-Bas)
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National Center For Child Health and Development
Affiliation as printed
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
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Essen University Hospital · University of Duisburg-Essen
Affiliation as printed
Institut Für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen] (Hufelandstraße 55, 45147 Essen - Allemagne)
Universität Duisburg-Essen = University of Duisburg-Essen [Essen] (Universitätsstraße 2, 45141 Essen - Allemagne)
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Tartu University Hospital · University of Tartu
Affiliation as printed
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
Tartu University Hospital (Ludvig Puusepa 8, 50406 Tartu Estonie - Estonie)
Tartu University Hospital [Tartu, Estonia] (Estonie)
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Hospital Universitario La Paz · Hospital La Paz Institute for Health Research · Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
Institute of Medical and Molecular Genetics, INGEMM-Idipaz, Madrid, Spain
CIBER de Enfermedades Raras (CIBERER) (Espagne)
IdiPaz - Hospital La Paz Institute for Health Research [Madrid, Spain] (Paseo de la Castellana, 261, Fuencarral-El Pardo, 28046 Madrid - Espagne)
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Affiliation as printed
Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
Vilnius University [Vilnius] (3 Universiteto St, LT-01513 Vilnius - Lituanie)
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Affiliation as printed
Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
Vilnius University [Vilnius] (3 Universiteto St, LT-01513 Vilnius - Lituanie)
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University of Campania "Luigi Vanvitelli"
Affiliation as printed
Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università Degli Studi Della Campania "Luigi Vanvitelli", Caserta, Italy
Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli (Viale Abramo Lincoln n. 5 - 81100 Caserta - Italie)
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Southampton General Hospital · Southampton Children's Hospital · University of Southampton
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, UK
Regional Centre for Paediatric Endocrinology, Faculty of Medicine, Southampton Children's Hospital, University of Southampton, Southampton, UK
Faculty of Medicine, Southampton General Hospital (Royaume-Uni)
University of Southampton (University Road, Southampton SO17 1BJ - Royaume-Uni)
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Affiliation as printed
Department of Clinical and Biological Science, School of Medicine, Centre for Hemoglobinopathies, AOU San Luigi Gonzaga, University of Turin, Turin, Italy
UNITO - Università degli studi di Torino = University of Turin (Via Verdi, 8 10124 Torino Italie - Italie)
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Affiliation as printed
Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
Tartu University Hospital [Tartu, Estonia] (Estonie)
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Ikerbasque · Hospital Txagorritxu · Hospital Universitario Araba
Affiliation as printed
Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Araba, Spain
Bioaraba Health Research Institute (IKERBASQUE. Basque Foundation for Science Plaza Euskadi 5 48009 Bilbao Spain - Espagne)
Hospital Universitario de Araba = Araba University Hospital (C/ Jose Atxotegi, s/n, 01009 Vitoria-Gasteiz, Álava, Araba - Espagne)
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Ikerbasque · Hospital Txagorritxu · Hospital Universitario Araba
Affiliation as printed
Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Araba, Spain
Bioaraba Health Research Institute (IKERBASQUE. Basque Foundation for Science Plaza Euskadi 5 48009 Bilbao Spain - Espagne)
Hospital Universitario de Araba = Araba University Hospital (C/ Jose Atxotegi, s/n, 01009 Vitoria-Gasteiz, Álava, Araba - Espagne)
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IRCCS Istituto Auxologico Italiano
Affiliation as printed
IRCCS Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy
Istituto Auxologico Italiano (France)
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IRCCS Istituto Auxologico Italiano
Affiliation as printed
IRCCS Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy
Istituto Auxologico Italiano (France)
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Princess Anne Hospital · University Hospital Southampton NHS Foundation Trust · University of Southampton
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, UK
Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Trust, Southampton, UK
PAH - Princess Anne Hospital [Southampton, UK] (Southampton, UK - Royaume-Uni)
University Hospital Southampton NHS Foundation Trust (University Hospital Southampton NHS Foundation Trust Tremona Road Southampton Hampshire SO16 6YD - Royaume-Uni)
University of Southampton (University Road, Southampton SO17 1BJ - Royaume-Uni)
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Tartu University Hospital · University of Tartu
Affiliation as printed
Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
Tartu University Hospital (Ludvig Puusepa 8, 50406 Tartu Estonie - Estonie)
Tartu University Hospital [Tartu, Estonia] (Estonie)
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University of Campania "Luigi Vanvitelli" · Institute of Genetics and Biophysics · National Research Council
Affiliation as printed
Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università Degli Studi Della Campania "Luigi Vanvitelli", Caserta, Italy
Institute of Genetics and Biophysics (IGB),"Adriano Buzzati-Traverso", Consiglio Nazionale Delle Ricerche (CNR), Naples, Italy
IGB - Istituto di Genetica e Biofisica “Adriano Buzzati Traverso” (Via Pietro Castellino 111, 80131 Naples - Italie)
Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli (Viale Abramo Lincoln n. 5 - 81100 Caserta - Italie)
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Ikerbasque · Hospital Txagorritxu · Hospital Universitario Araba
Affiliation as printed
Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Araba, Spain
Bioaraba Health Research Institute (IKERBASQUE. Basque Foundation for Science Plaza Euskadi 5 48009 Bilbao Spain - Espagne)
Hospital Universitario de Araba = Araba University Hospital (C/ Jose Atxotegi, s/n, 01009 Vitoria-Gasteiz, Álava, Araba - Espagne)
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Aston University · University of Cambridge
Affiliation as printed
Aston Medical School, Aston University, Birmingham, UK
Department of Medical Genetics, University of Cambridge, Cambridge, UK
Aston University [Birmingham] (Birmingham, B4 7ET - Royaume-Uni)
CAM - University of Cambridge [UK] (The Old Schools, Trinity Lane, Cambridge CB2 1TN - Royaume-Uni)
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Hospital Universitario La Paz · Hospital La Paz Institute for Health Research · Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
Institute of Medical and Molecular Genetics, INGEMM-Idipaz, Madrid, Spain
CIBER de Enfermedades Raras (CIBERER) (Espagne)
IdiPaz - Hospital La Paz Institute for Health Research [Madrid, Spain] (Paseo de la Castellana, 261, Fuencarral-El Pardo, 28046 Madrid - Espagne)
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Inserm · Sorbonne Université · Hôpital Armand-Trousseau · Assistance Publique – Hôpitaux de Paris · Centre de Recherche Saint-Antoine
Affiliation as printed
Centre de Recherche Saint Antoine, Endocrinologie Moléculaire et Pathologies d'empreinte, INSERMSorbonne Université, Hôpital Armand TrousseauAPHP, 75012, Paris, France
CHU Trousseau [APHP] (26 Avenue du Dr Arnold Netter, 75012 Paris - France)
CRSA - Centre de Recherche Saint-Antoine (Bâtiment Kourilsky 34 rue Crozatier 75012 PARIS Sorbonne Université 27 rue Chaligny 75012 PARIS - France)
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Affiliation as printed
Institute for Human Genetics and Genome Medicine. Faculty of Medicine, RWTH University Aachen, Aachen, Germany
Helmholtz-Institute for Biomedical Engineering [RWTH Aachen University] (France)
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam UMC - Amsterdam University Medical Centers (1105 AZ Amsterdam - Pays-Bas)
UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam (Spui 21 1012 WX Amsterdam - Pays-Bas)
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University of Copenhagen · Copenhagen University Hospital · Rigshospitalet · Kennedy Center
Affiliation as printed
Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Copenhagen University Hospital (Danemark)
UCPH - University of Copenhagen = Københavns Universitet (Nørregade 10, 1165 København, Danemark - Danemark)
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