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A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus

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Abstract

The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient neonatal diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.

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Abbreviations

BWS:

Beckwith–Wiedemann syndrome

DMR:

differentially methylated region

IUGR:

Intra-uterine growth retardation

LOM:

Loss of methylation

MS-PCR:

Methylation-specific PCR

TNDM:

Transient neonatal diabetes mellitus

UPD:

Uniparental disomy

WRGL:

Wessex Regional Genetics Laboratory

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Acknowledgments

The authors thank Paul Strike for statistical analysis, Rinki Singh for helpful discussions, and Sven Poerksen (Department of Paediatrics, Glostrup Hospital, Glostrup, Denmark), Guy Hendrickx (Department of Paediatrics, Free University of Brussels, Jette, Belgium), Tracy Tinklin (Department of Paediatrics, Derby Children’s Hospital, UK). DJGM was funded by Diabetes UK, and PRN by the University of Bergen and Haukeland University Hospital.

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Authors and Affiliations

  1. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK

    D. J. G. Mackay & D. O. Robinson

  2. Human Genetics Division, University of Southampton, Southampton, UK

    D. J. G. Mackay & I. K. Temple

  3. Clinical Genetics, The Kennedy Institute, National Eye Clinic, Glostrup, Denmark

    S. E. Boonen

  4. Department of Clinical Genetics, St Mary’s Hospital, Manchester, UK

    J. Clayton-Smith

  5. Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK

    J. Goodship

  6. Medical Genetics Laboratory Centre, The Kennedy Institute, National Eye Clinic, Glostrup, Denmark

    J. M. D. Hahnemann

  7. Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    S. G. Kant

  8. Department of Clinical Medicine, University of Bergen, Bergen, Norway

    P. R. Njølstad

  9. Department of Paediatrics, Haukeland University Hospital, Bergen, Norway

    P. R. Njølstad

  10. Department of Genetics and Pediatrics, University of Alabama at Birmingham, Birmingham, USA

    N. H. Robin

  11. Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany

    R. Siebert

  12. University of Bristol and Bristol Royal Hospital for Children, Bristol, UK

    J. P. H. Shield

  13. National Genetics Reference Laboratory Wessex, Salisbury, UK

    H. E. White

  14. Wessex Clinical Genetics Service, The Princess Anne Hospital, Southampton, UK

    I. K. Temple

Authors
  1. D. J. G. Mackay
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  2. S. E. Boonen
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  3. J. Clayton-Smith
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  4. J. Goodship
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  5. J. M. D. Hahnemann
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  6. S. G. Kant
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  7. P. R. Njølstad
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  8. N. H. Robin
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  9. D. O. Robinson
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  10. R. Siebert
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  11. J. P. H. Shield
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  12. H. E. White
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  13. I. K. Temple
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Correspondence to D. J. G. Mackay.

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Mackay, D.J.G., Boonen, S.E., Clayton-Smith, J. et al. A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Hum Genet 120, 262–269 (2006). https://doi.org/10.1007/s00439-006-0205-2

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  • DOI: https://doi.org/10.1007/s00439-006-0205-2

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