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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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