Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome

• Published in: European journal of human genetics : EJHG Vol. 17; no. 5; pp. 611 - 619
• Main Authors: BLIEK, Jet, VERDE, Gaetano, FISCHETTO, Rita, LALATTA, Faustina, GIORDANO, Lucio, FERRARI, Paola, CUBELLIS, Maria Vittoria, LARIZZA, Lidia, TEMPLE, I. Karen, MANNENS, Marcel M. A. M, MACKAY, Deborah J. G, RICCIO, Andrea, CALLAWAY, Jonathan, MAAS, Saskia M, DE CRESCENZO, Agostina, SPARAGO, Angela, CERRATO, Flavia, RUSSO, Silvia, FERRAIUOLO, Serena, MICHELA RINALDI, Maria
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-05-2009
• Subjects: Beckwith-Wiedemann syndrome; Beckwith-Wiedemann Syndrome - genetics; Beckwith-Wiedemann Syndrome - pathology; Biological and medical sciences; Birth weight; Cell Cycle Proteins - genetics; Chromogranins; Chromosomes; Classical genetics, quantitative genetics, hybrids; Defects; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diagnosis; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; DNA Mutational Analysis; Epigenetics; Female; Fundamental and applied biological sciences. Psychology; Gene expression; General aspects. Genetic counseling; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomic Imprinting; GTP-Binding Protein alpha Subunits, Gs - genetics; Human; Humans; Imprinting; KCNQ1OT1 protein; Laboratories; Male; Medical genetics; Medical sciences; Methylation; Molecular and cellular biology; Mutation; Neonates; Pediatrics; Polymerase Chain Reaction; Polymorphism, Genetic; Potassium channels (voltage-gated); Pseudohypoparathyroidism; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics; United Kingdom > UK; Italy; Netherlands; Beckwith-Wiedemann syndrome; Multiple; imprinting; Beckwith-Wiedemann syndrome (BWS); Congenital disease; Genetic disease; Genomic imprinting; Abdominal disease; KCNQ1OT1; Genetics; imprinting disorder; hypomethylation of imprinted loci (HIL); Locus; Methylation
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2008.233

Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally methylated loci and that the clinical presentation of these complex cases may reflect the loci and tissues affected with the epigenetic abnormalities.