title: 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=2), hypomethylation at the H19 3CTCF-binding site (n=1), hypermethylation at NDN (n=1) and hypermethylation at IGF2 (n=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.
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. sbens@medgen.uni-kiel.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Bens
authors.forename: Andrea
authors.initials: A
authors.lastname: Haake
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Judith
authors.initials: J
authors.lastname: Leohold
authors.forename: Julia
authors.initials: J
authors.lastname: Kolarova
authors.forename: Inga
authors.initials: I
authors.lastname: Vater
authors.forename: Felix G
authors.initials: FG
authors.lastname: Riepe
authors.forename: Karin
authors.initials: K
authors.lastname: Buiting
authors.forename: Thomas
authors.initials: T
authors.lastname: Eggermann
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Konrad
authors.initials: K
authors.lastname: Platzer
authors.forename: Dirk
authors.initials: D
authors.lastname: Prawitt
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019175:DNA Methylation; D005192:Family Health; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013577:Syndrome