Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci
Open Access
- 14 September 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 18 (24), 4724-4733
- https://doi.org/10.1093/hmg/ddp435
Abstract
Genomic imprinting plays an important role in mammalian development. Loss of imprinting (LOI) through loss (LOM) or gain (GOM) of methylation is involved in many human disorders and cancers. The imprinted 11p15 region is crucial for the control of foetal growth and LOI at this locus is implicated in two clinically opposite disorders: Beckwith Wiedemann syndrome (BWS) with foetal overgrowth associated with an enhanced tumour risk and Russell–Silver syndrome (RSS) with intrauterine and postnatal growth restriction. So far, only a few studies have assessed multilocus LOM in human imprinting diseases. To investigate multilocus LOI syndrome, we studied the methylation status of five maternally and two paternally methylated loci in a large series (n = 167) of patients with 11p15-related foetal growth disorders. We found that 9.5% of RSS and 24% of BWS patients showed multilocus LOM at regions other than ICR1 and ICR2 11p15, respectively. Moreover, over two third of multilocus LOM RSS patients also had LOM at a second paternally methylated locus, DLK1/GTL2 IG-DMR. No additional clinical features due to LOM of other loci were found suggesting an (epi)dominant effect of the 11p15 LOM on the clinical phenotype for this series of patients. Surprisingly, four patients displayed LOM at both ICR1 and ICR2 11p15. Three of them had a RSS and one a BWS phenotype. Our results show for the first time that multilocus LOM can also concern RSS patients. Moreover, LOM can involve both paternally and maternally methylated loci in the same patient.Keywords
This publication has 49 references indexed in Scilit:
- Germline Mutation in NLRP2 (NALP2) in a Familial Imprinting Disorder (Beckwith-Wiedemann Syndrome)PLoS Genetics, 2009
- Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndromeEuropean Journal of Human Genetics, 2008
- Isolated imprinting mutation of the DLK1/GTL2 locus associated with a clinical presentation of maternal uniparental disomy of chromosome 14Journal of Medical Genetics, 2007
- Epigenetic reprogramming and imprinting in origins of diseaseReviews in Endocrine and Metabolic Disorders, 2007
- The Testis-Specific Factor CTCFL Cooperates with the Protein Methyltransferase PRMT7 in H19 Imprinting Control Region MethylationPLoS Biology, 2006
- The epigenetic imprinting defect of patients with Beckwith--Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 regionJournal of Medical Genetics, 2006
- Epimutation of the TNDM locus and the Beckwith–Wiedemann syndrome centromeric locus in individuals with transient neonatal diabetes mellitusHuman Genetics, 2006
- Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndromeNature Genetics, 2005
- Targeted mutation of the DNA methyltransferase gene results in embryonic lethalityCell, 1992
- Intrauterine growth of live-born Caucasian infants at sea level: Standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeksThe Journal of Pediatrics, 1969