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Imprinting disorders

Nature Reviews Disease Primers volume 9, Article number: 33 (2023) Cite this article

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Abstract

Imprinting disorders (ImpDis) are congenital conditions that are characterized by disturbances of genomic imprinting. The most common individual ImpDis are Prader–Willi syndrome, Angelman syndrome and Beckwith–Wiedemann syndrome. Individual ImpDis have similar clinical features, such as growth disturbances and developmental delay, but the disorders are heterogeneous and the key clinical manifestations are often non-specific, rendering diagnosis difficult. Four types of genomic and imprinting defect (ImpDef) affecting differentially methylated regions (DMRs) can cause ImpDis. These defects affect the monoallelic and parent-of-origin-specific expression of imprinted genes. The regulation within DMRs as well as their functional consequences are mainly unknown, but functional cross-talk between imprinted genes and functional pathways has been identified, giving insight into the pathophysiology of ImpDefs. Treatment of ImpDis is symptomatic. Targeted therapies are lacking owing to the rarity of these disorders; however, personalized treatments are in development. Understanding the underlying mechanisms of ImpDis, and improving diagnosis and treatment of these disorders, requires a multidisciplinary approach with input from patient representatives.

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Fig. 1: Molecular disturbances associated with imprinting disorders.
Fig. 2: Inheritance of ImpDis.
Fig. 3: Imprinting dynamics during development.
Fig. 4: Cross-talk between imprinted loci.
Fig. 5: Major clinical findings in ImpDis.
Fig. 6: Molecular diagnostic work-up for ImpDis.

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Acknowledgements

The authors thank the patients and their families for the support of their research activity. The authors are supported by the following grants: Deutsche Forschungsgemeinschaft to T.E. (EG 115/13-1). Instituto de Salud Carlos III (ISCIIII) of the Ministry of Economy and Competitiveness (Spain) cofinanced by European Regional Development Fund (PI20/00950) and the Department of Health of the Basque Government (GV2021/111056) to G.P.d.N. J.M.K. is supported by a Damon Runyon Clinical Investigator Award supported by the Damon Runyon Cancer Research Foundation (105-19), Alex’s Lemonade Stand Foundation and the Lorenzo “Turtle” Sartini Jr Endowed Chair in Beckwith–Wiedemann Syndrome Research. A.R. is supported by Associazione Italiana per la Ricerca sul Cancro — AIRC IG 2020N. 24405. E.R.M. thanks the NIHR Cambridge Biomedical Research Centre (NIHR203312) and RoseTrees Trust for research support. The University of Cambridge has received salary support for E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. M.K. is funded by the Japan Agency for Medical Research and Development (AMED) (20ek0109373h0003, 22ek0109587).

Author information

Authors and Affiliations

  1. Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany

    Thomas Eggermann, Matthias Begemann & Miriam Elbracht

  2. School of Biological Sciences, University of East Anglia, Norwich, UK

    David Monk

  3. Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Research Health Institute, Araba University Hospital–Txagorritxu, Vitoria-Gasteiz, Spain

    Guiomar Perez de Nanclares

  4. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

    Masayo Kagami

  5. Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpital Armand Trousseau, Endocrinologie Moléculaire et Pathologies d’Empreinte, Paris, France

    Eloïse Giabicani

  6. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Università della Campania Luigi Vanvitelli, Caserta, Italy

    Andrea Riccio

  7. Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy

    Andrea Riccio

  8. Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Zeynep Tümer

  9. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Zeynep Tümer

  10. Division of Human Genetics and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Departments of Pediatrics and Genetics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jennifer M. Kalish

  11. Centre de Référence Maladies Rares PRADORT (syndrome de PRADer-Willi et autres Obésités Rares avec Troubles du comportement alimentaire), Hôpital des Enfants, CHU Toulouse, Toulouse, France

    Maithé Tauber

  12. Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity) INSERM UMR1291 – CNRS UMR5051 – Université Toulouse III, Toulouse, France

    Maithé Tauber

  13. Department of Pediatrics, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Jessica Duis

  14. Division of Clinical and Metabolic Genetics, Department of Paediatrics and Genetics and Genome Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada

    Rosanna Weksberg

  15. Institute of Medical Sciences and Department of Molecular Genetics, University of Toronto, Toronto, Canada

    Rosanna Weksberg

  16. Department of Medical Genetics, University of Cambridge, Cambridge, UK

    Eamonn R. Maher

Authors
  1. Thomas Eggermann
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  2. David Monk
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  3. Guiomar Perez de Nanclares
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  4. Masayo Kagami
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  5. Eloïse Giabicani
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  6. Andrea Riccio
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  7. Zeynep Tümer
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  8. Jennifer M. Kalish
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  9. Maithé Tauber
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  10. Jessica Duis
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  11. Rosanna Weksberg
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  12. Eamonn R. Maher
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  13. Matthias Begemann
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  14. Miriam Elbracht
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Contributions

Introduction (T.E., M.B. and M.E.); Epidemiology (T.E., M.B. and M.E.); Mechanisms/pathophysiology (D.M., A.R. and Z.T.); Diagnosis, screening and prevention (M.E., M.B., M.K., G.P.d.N., E.G., E.R.M. and R.W.); Management (E.G., E.R.M., R.W., M.T., J.D., J.M.K. and M.E.); Quality of life (T.E. and M.E.); Outlook (all); Overview of Primer (T.E.).

Corresponding author

Correspondence to Thomas Eggermann.

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Nature Reviews Disease Primers thanks J. LaSalle, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders: https://ern-ithaca.eu

European Reference Network on Rare Endocrine Conditions: https://endo-ern.eu

FACE2GENE: https://face2gene.com

GestaltMatcherDB: https://gestaltmatcher.org

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Eggermann, T., Monk, D., de Nanclares, G.P. et al. Imprinting disorders. Nat Rev Dis Primers 9, 33 (2023). https://doi.org/10.1038/s41572-023-00443-4

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