Original Investigation

Human Genetics

, Volume 120, Issue 2, pp 262-269

First online:

A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus

  • D. J. G. MackayAffiliated withWessex Regional Genetics Laboratory, Salisbury District HospitalHuman Genetics Division, University of Southampton Email author 
  • , S. E. BoonenAffiliated withClinical Genetics, The Kennedy Institute, National Eye Clinic
  • , J. Clayton-SmithAffiliated withDepartment of Clinical Genetics, St Mary’s Hospital
  • , J. GoodshipAffiliated withInstitute of Human Genetics, International Centre for Life
  • , J. M. D. HahnemannAffiliated withMedical Genetics Laboratory Centre, The Kennedy Institute, National Eye Clinic
  • , S. G. KantAffiliated withCenter for Human and Clinical Genetics, Leiden University Medical Center
  • , P. R. NjølstadAffiliated withDepartment of Clinical Medicine, University of BergenDepartment of Paediatrics, Haukeland University Hospital
  • , N. H. RobinAffiliated withDepartment of Genetics and Pediatrics, University of Alabama at Birmingham
  • , D. O. RobinsonAffiliated withWessex Regional Genetics Laboratory, Salisbury District Hospital
    • , R. SiebertAffiliated withInstitute of Human Genetics, University Hospital Schleswig-Holstein
    • , J. P. H. ShieldAffiliated withUniversity of Bristol and Bristol Royal Hospital for Children
    • , H. E. WhiteAffiliated withNational Genetics Reference Laboratory Wessex
    • , I. K. TempleAffiliated withHuman Genetics Division, University of SouthamptonWessex Clinical Genetics Service, The Princess Anne Hospital

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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.