Frequency and characterization of DNA methylation defects in children born SGA

Abstract

Various genes located at imprinted loci and regulated by epigenetic mechanisms are involved in the control of growth and differentiation. The broad phenotypic variability of imprinting disorders suggests that individuals with inborn errors of imprinting might remain undetected among patients born small for gestational age (SGA). We evaluated quantitative DNA methylation analysis at differentially methylated regions (DMRs) of 10 imprinted loci (PLAGL1, IGF2R DMR2, GRB10, H19 DMR, IGF2, MEG3, NDN, SNRPN, NESP, NESPAS) by bisulphite pyrosequencing in 98 patients born SGA and 50 controls. For IGF2R DMR2, methylation patterns of additional 47 parent pairs and one mother (95 individuals) of patients included in the SGA cohort were analyzed. In six out of 98 patients born SGA, we detected DNA methylation changes at single loci. In one child, the diagnosis of upd(14)mat syndrome owing to an epimutation of the MEG3 locus in 14q32 could be established. The remaining five patients showed hypomethylation at GRB10 (n ¼ 2), hypomethylation at the H19 3CTCF-binding site (n ¼ 1), hypermethylation at NDN (n ¼ 1) and hypermethylation at IGF2 (n ¼ 1). IGF2R DMR2 hypermethylation was detected in five patients, six parents of patients in the SGA cohort and two controls. We conclude that aberrant methylation at imprinted loci in children born SGA exists but seems to be rare if known imprinting syndromes are excluded. Further investigations on the physiological variations and the functional consequences of the detected aberrant methylation are necessary before final conclusions on the clinical impact can be drawn.

Phenotypic Spectrum and Extent of DNA Methylation Defects Associated with Multilocus Imprinting Disturbances

“…No epimutations affecting ZDBF2 were identified Third, we studied a cohort of 52 SGA-born children (SGA cohort) enriched for patients with a phenotype at the severe end of the spectrum (i.e., lack of catchup growth and/or developmental delay) for aberrant DNA methylation at the ZDBF2 and FAM50B loci applying the Illumina Infinium HumanMethylation450 BeadChip. These patients were previously shown to be not affected by classical imprinting disorders [25]. None of these patients displayed aberrant DNA methylation values at the FAM50B locus (Supplementary Figure S4 & Supplementary Table S2E).…”

Epimutation profiling in Beckwith-Wiedemann syndrome: relationship with assisted reproductive technology

“…As found in our previous smaller study, ART-conceived children were significantly over-represented among BWS ME + patients but more extensive methylation profiling using the CpG methylation array did not clearly differentiate between post-ART and naturally conceived BWS patients. Previously methylation profiling at imprinted loci in ART-conceived children without imprinting disorders has shown no generalised tendency to methylation changes [ 37 ]. We investigated a cohort with IC2 epimutations and though it could be argued that such cases might have been susceptible to ART-associated imprinting errors, only a minority had a ME + epigenotype.…”

In vivo Investigations of the Effect of Short- and Long-Term Recombinant Growth Hormone Treatment on DNA-Methylation in Humans

“…Peripheral blood (PB) samples from 54 children born SGA, defined as birth length and/or birth weight -2SD below the mean for gestational age according to the reference data published by Niklasson et al [ 24 ], were included. The cohort has been recruited in the framework of the consortium “Diseases caused by imprinting defects: clinical spectrum and pathogenetic mechanisms” and partially overlaps with the previously described cohort of SGA born children studied for their DNA-methylation pattern at 10 imprinted loci by bisulfite pyrosequencing [ 25 ]. Of note, the children with evidence for DNA-methylation defects at the loci IGF2 , H19 , GRB10 , MEG3 and NDN in the latter study were excluded from the present study.…”