Human Genetics

, Volume 120, Issue 2, pp 262–269

A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus

  • D. J. G. Mackay
  • S. E. Boonen
  • J. Clayton-Smith
  • J. Goodship
  • J. M. D. Hahnemann
  • S. G. Kant
  • P. R. Njølstad
  • N. H. Robin
  • D. O. Robinson
  • R. Siebert
  • J. P. H. Shield
  • H. E. White
  • I. K. Temple
Original Investigation

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.

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

Supplementary material

439_2006_205_MOESM1_ESM.pdf (133 kb)
Supplementary material 1
439_2006_205_MOESM2_ESM.doc (20 kb)
Supplementary material 2
439_2006_205_MOESM3_ESM.doc (35 kb)
Supplementary material 3

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • D. J. G. Mackay
    • 1
    • 2
  • S. E. Boonen
    • 3
  • J. Clayton-Smith
    • 4
  • J. Goodship
    • 5
  • J. M. D. Hahnemann
    • 6
  • S. G. Kant
    • 7
  • P. R. Njølstad
    • 8
    • 9
  • N. H. Robin
    • 10
  • D. O. Robinson
    • 1
  • R. Siebert
    • 11
  • J. P. H. Shield
    • 12
  • H. E. White
    • 13
  • I. K. Temple
    • 2
    • 14
  1. 1.Wessex Regional Genetics LaboratorySalisbury District HospitalSalisburyUK
  2. 2.Human Genetics DivisionUniversity of SouthamptonSouthamptonUK
  3. 3.Clinical GeneticsThe Kennedy Institute, National Eye ClinicGlostrupDenmark
  4. 4.Department of Clinical GeneticsSt Mary’s HospitalManchesterUK
  5. 5.Institute of Human GeneticsInternational Centre for LifeNewcastle upon TyneUK
  6. 6.Medical Genetics Laboratory CentreThe Kennedy Institute, National Eye ClinicGlostrupDenmark
  7. 7.Center for Human and Clinical GeneticsLeiden University Medical CenterLeidenThe Netherlands
  8. 8.Department of Clinical MedicineUniversity of BergenBergenNorway
  9. 9.Department of PaediatricsHaukeland University HospitalBergenNorway
  10. 10.Department of Genetics and PediatricsUniversity of Alabama at BirminghamBirminghamUSA
  11. 11.Institute of Human GeneticsUniversity Hospital Schleswig-HolsteinKielGermany
  12. 12.University of Bristol and Bristol Royal Hospital for ChildrenBristolUK
  13. 13.National Genetics Reference Laboratory WessexSalisburyUK
  14. 14.Wessex Clinical Genetics ServiceThe Princess Anne HospitalSouthamptonUK

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