title: A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus.
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.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK.
authors.forename: D J G
authors.initials: DJ
authors.lastname: Mackay
authors.forename: S E
authors.initials: SE
authors.lastname: Boonen
authors.forename: J
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: J
authors.initials: J
authors.lastname: Goodship
authors.forename: J M D
authors.initials: JM
authors.lastname: Hahnemann
authors.forename: S G
authors.initials: SG
authors.lastname: Kant
authors.forename: P R
authors.initials: PR
authors.lastname: Njølstad
authors.forename: N H
authors.initials: NH
authors.lastname: Robin
authors.forename: D O
authors.initials: DO
authors.lastname: Robinson
authors.forename: R
authors.initials: R
authors.lastname: Siebert
authors.forename: J P H
authors.initials: JP
authors.lastname: Shield
authors.forename: H E
authors.initials: HE
authors.lastname: White
authors.forename: I K
authors.initials: IK
authors.lastname: Temple
mesh_terms: D001724:Birth Weight; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D019175:DNA Methylation; D003920:Diabetes Mellitus / Q000235:genetics*; D005220:Fathers; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009035:Mothers