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Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders

Authors

  • Rebecca L. Poole,

    1. Faculty of Medicine, University of Southampton, Southampton, UK
    2. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
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  • Louise E. Docherty,

    1. Faculty of Medicine, University of Southampton, Southampton, UK
    2. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
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  • Abeer Al Sayegh,

    1. Faculty of Medicine, University of Southampton, Southampton, UK
    2. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
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    • Abeer Al Sayegh's present address is Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, P.O. Box 38, Alkoudh, 123, Sultanate of Oman
  • Almuth Caliebe,

    1. Faculty of Medicine, University of Southampton, Southampton, UK
    2. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
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    • Almuth Caliebe's present address is Institut für Humangenetik des Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany
  • Claire Turner,

    1. Peninsula Genetic Service, Royal Devon and Exeter Hospital, Exeter, UK
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  • Emma Baple,

    1. Centre for Human Genetics, St. George's, University of London, London, UK
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  • Emma Wakeling,

    1. North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, UK
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  • Lucy Harrison,

    1. Faculty of Medicine, University of Southampton, Southampton, UK
    2. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
    3. Comprehensive Local Research Network (Hampshire & Isle of Wight), Hampshire, UK
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  • Anna Lehmann,

    1. Faculty of Medicine, University of Southampton, Southampton, UK
    2. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
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    • Anna Lehmann's present address is South West Thames Regional Genetics Service, St George's, University of London, UK
  • I. Karen Temple,

    Corresponding author
    1. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
    • Faculty of Medicine, University of Southampton, Southampton, UK
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  • Deborah J.G. Mackay,

    1. Faculty of Medicine, University of Southampton, Southampton, UK
    2. Wessex Genetics Service, University Hospital Trust, Southampton, and Salisbury Hospital NHS Foundation Trust, Salisbury, UK
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  • On behalf of the International Clinical Imprinting Consortium


  • Conflict of interests: None.
  • Consortium members are listed as an Appendix in the Supplementary Information.

Correspondence to:

Dr. Professor I.K. Temple, M.D., Wessex Clinical Genetics Service, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK.

E-mail: i.k.temple@soton.ac.uk

Abstract

Imprinting disorders are associated with mutations and epimutations affecting imprinted genes, that is those whose expression is restricted by parent of origin. Their diagnosis is challenging for two reasons: firstly, their clinical features, particularly prenatal and postnatal growth disturbance, are heterogeneous and partially overlapping; secondly, their underlying molecular defects include mutation, epimutation, copy number variation, and chromosomal errors, and can be further complicated by somatic mosaicism and multi-locus methylation defects. It is currently unclear to what extent the observed phenotypic heterogeneity reflects the underlying molecular pathophysiology; in particular, the molecular and clinical diversity of multilocus methylation defects remains uncertain. To address these issues we performed comprehensive methylation analysis of imprinted genes in a research cohort of 285 patients with clinical features of imprinting disorders, with or without a positive molecular diagnosis. 20 of 91 patients (22%) with diagnosed epimutations had methylation defects of additional imprinted loci, and the frequency of developmental delay and congenital anomalies was higher among these patients than those with isolated epimutations, indicating that hypomethylation of multiple imprinted loci is associated with increased diversity of clinical presentation. Among 194 patients with clinical features of an imprinting disorder but no molecular diagnosis, we found 15 (8%) with methylation anomalies, including missed and unexpected molecular diagnoses. These observations broaden the phenotypic and epigenetic definitions of imprinting disorders, and show the importance of comprehensive molecular testing for patient diagnosis and management. © 2013 Wiley Periodicals, Inc.

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