Contract grant sponsors: Fundació La Marató de TV3 (101130); FIS-program (I3SNS-CA10/01056); I3SNS Program of the Spanish Ministry of Health (CP03/0064; SIVI 1395/09); Fundacion Eugenio Rodriguez Pascual and the Instituto de Salud Carlos III (PI10/0148).
Genome-Wide Allelic Methylation Analysis Reveals Disease-Specific Susceptibility to Multiple Methylation Defects in Imprinting Syndromes
Article first published online: 19 FEB 2013
© 2013 Wiley Periodicals, Inc.
Volume 34, Issue 4, pages 595–602, April 2013
How to Cite
Court, F., Martin-Trujillo, A., Romanelli, V., Garin, I., Iglesias-Platas, I., Salafsky, I., Guitart, M., Perez de Nanclares, G., Lapunzina, P. and Monk, D. (2013), Genome-Wide Allelic Methylation Analysis Reveals Disease-Specific Susceptibility to Multiple Methylation Defects in Imprinting Syndromes. Hum. Mutat., 34: 595–602. doi: 10.1002/humu.22276
Communicated by Nancy B. Spinner
- Issue published online: 20 MAR 2013
- Article first published online: 19 FEB 2013
- Accepted manuscript online: 18 JAN 2013 09:50AM EST
- Manuscript Accepted: 7 JAN 2013
- Manuscript Received: 2 OCT 2012
- Fundació La Marató de TV3. Grant Number: 101130
- FIS-program. Grant Number: I3SNS-CA10/01056
- I3SNS Program of the Spanish Ministry of Health. Grant Numbers: CP03/0064, SIVI 1395/09
- Fundacion Eugenio Rodriguez Pascual and the Instituto de Salud Carlos III. Grant Number: PI10/0148
- multiple hypo-methylation syndromes
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.