title: Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes.
abstract: Genomic imprinting is the parent-of-origin-specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith-Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver-Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader-Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance.
authors: Imprinting and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Franck
authors: F
authors: Court
authors: Alex
authors: A
authors: Martin-Trujillo
authors: Valeria
authors: V
authors: Romanelli
authors: Intza
authors: I
authors: Garin
authors: Isabel
authors: I
authors: Iglesias-Platas
authors: Ira
authors: I
authors: Salafsky
authors: Miriam
authors: M
authors: Guitart
authors: Guiomar
authors: G
authors: Perez de Nanclares
authors: Pablo
authors: P
authors: Lapunzina
authors: David
authors: D
authors: Monk
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001506:Beckwith-Wiedemann Syndrome / Q000175:diagnosis / Q000235:genetics; D001665:Binding Sites; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D009154:Mutation; D011218:Prader-Willi Syndrome / Q000175:diagnosis / Q000235:genetics; D011546:Pseudohypoaldosteronism / Q000175:diagnosis / Q000235:genetics; D056730:Silver-Russell Syndrome / Q000175:diagnosis / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics
chemical_list: D015534:Trans-Activators