First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders
Clinical Epigenetics, vol. 14, pp. 143
Abstract
BACKGROUND: Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses. RESULTS: We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories. CONCLUSIONS: Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.
Authors 29
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Wessex Regional Genetics Laboratory · University of Southampton
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
Wessex Regional Genetics Laboratory, Salisbury, SP2 8BJ, UK
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Amsterdam University Medical Centers
Affiliation as printed
Department of Human Genetics, Laboratory for Genome Diagnostics, Amsterdam UMC, Amsterdam, Netherlands
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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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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases · ERN ITHACA
Affiliation as printed
CIBERER- ISCIII and INGEMM, Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Madrid, Spain
ERN-Ithaca, European Reference Networks, Brussels, Belgium
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
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Hospital Txagorritxu · Hospital Universitario Araba
Affiliation as printed
Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, C/Jose Atxotegi s/n, 01009, Vitoria-Gasteiz, Spain
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Inserm · Sorbonne Université · Centre de Recherche Saint-Antoine
Affiliation as printed
INSERM, UMR 938, Centre de Recherche Saint-Antoine (CRSA), APHP Hôpital Trousseau, Sorbonne Université, 75012, Paris, France
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Inserm · Sorbonne Université · Centre de Recherche Saint-Antoine
Affiliation as printed
INSERM, UMR 938, Centre de Recherche Saint-Antoine (CRSA), APHP Hôpital Trousseau, Sorbonne Université, 75012, Paris, France
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Affiliation as printed
Institute of Human Genetics, University of Hamburg, Hamburg, Germany
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Affiliation as printed
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
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Wessex Regional Genetics Laboratory · University of Southampton
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
Wessex Regional Genetics Laboratory, Salisbury, SP2 8BJ, UK
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Wessex Regional Genetics Laboratory · University of Southampton
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
Wessex Regional Genetics Laboratory, Salisbury, SP2 8BJ, UK
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Amsterdam University Medical Centers
Affiliation as printed
Department of Human Genetics, Laboratory for Genome Diagnostics, Amsterdam UMC, Amsterdam, Netherlands
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Centre Hospitalier Universitaire de Toulouse · Hôpital des Enfants
Affiliation as printed
Centre de Référence du Syndrome de Prader-Willi et Autres Obésités Avec Troubles du Comportement Alimentaire, Unité d'Endocrinologie, Obésité, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants CHU Toulouse, Toulouse, France
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Centre Hospitalier Universitaire de Toulouse · Hôpital des Enfants
Affiliation as printed
Centre de Référence du Syndrome de Prader-Willi et Autres Obésités Avec Troubles du Comportement Alimentaire, Unité d'Endocrinologie, Obésité, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants CHU Toulouse, Toulouse, France
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Centre Hospitalier Universitaire de Toulouse
Affiliation as printed
Laboratoire de Génétique Médicale, Institut Fédératif de Biologie CHU Toulouse, Toulouse, France
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Centre Hospitalier Universitaire de Toulouse
Affiliation as printed
Laboratoire de Génétique Médicale, Institut Fédératif de Biologie CHU Toulouse, Toulouse, France
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases · ERN ITHACA
Affiliation as printed
CIBERER- ISCIII and INGEMM, Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Madrid, Spain
ERN-Ithaca, European Reference Networks, Brussels, Belgium
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases · ERN ITHACA
Affiliation as printed
CIBERER- ISCIII and INGEMM, Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Madrid, Spain
ERN-Ithaca, European Reference Networks, Brussels, Belgium
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
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University of Copenhagen · Copenhagen University Hospital · Rigshospitalet · Kennedy Center
Affiliation as printed
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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University of Campania "Luigi Vanvitelli" · Institute of Genetics and Biophysics
Affiliation as printed
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Caserta, Italy
Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' CNR, Naples, Italy
Institute of Genetics and Biophysics 'Adriano Buzzati–Traverso' CNR, Naples, Italy
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Affiliation as printed
Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK
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Essen University Hospital · University of Duisburg-Essen
Affiliation as printed
Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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IRCCS Istituto Auxologico Italiano
Affiliation as printed
Medical Cytogenetics and Molecular Genetics Laboratory, Centro di Ricerche e Tecnologie Biomediche, Istituto Auxologico Italiano, IRCCS, Milan, Italy
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IRCCS Istituto Auxologico Italiano
Affiliation as printed
Medical Cytogenetics and Molecular Genetics Laboratory, Centro di Ricerche e Tecnologie Biomediche, Istituto Auxologico Italiano, IRCCS, Milan, Italy
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Affiliation as printed
ERN-Ithaca, European Reference Networks, Brussels, Belgium
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University Hospital Southampton NHS Foundation Trust · University of Southampton
Affiliation as printed
Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
Wessex Clinical Genetics Service, University Hospital Southampton, Southampton, UK
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Hamamatsu University · Hamamatsu University School of Medicine · Hamamatsu Medical Center
Affiliation as printed
Department of Pediatrics, Hamamatsu Medical Center and Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases · ERN ITHACA
Affiliation as printed
CIBERER- ISCIII and INGEMM, Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Madrid, Spain
ERN-Ithaca, European Reference Networks, Brussels, Belgium
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany. teggermann@ukaachen.de
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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