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Eur J Hum Genet. 2015 Feb;23(2):180-8. doi: 10.1038/ejhg.2014.72. Epub 2014 May 7.

Novel deletions affecting the MEG3-DMR provide further evidence for a hierarchical regulation of imprinting in 14q32.

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Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Institute of Human Genetics, RWTH Aachen, Aachen, Germany.
MRC Holland, Amsterdam, The Netherlands.
Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
Department of Neonatology and Pediatric Intensive Care, Childrens's Hospital, University of Cologne, Cologne, Germany.
1] National Centre for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin, Ireland [2] School of Medicine and Medical Science University College, Dublin, Ireland.
Institute of Human Genetics, University of Cologne, Cologne, Germany.


The imprinted region on chromosome 14q32 harbors several maternally or paternally expressed genes as well as two DMRs (differentially methylated regions), the IG-DMR and the MEG3-DMR, which both act as imprinting control centers. Genetic aberrations affecting the imprinted gene cluster in 14q32 result in distinct phenotypes, known as maternal or paternal uniparental disomy 14 phenotypes (upd(14)mat, upd(14)pat). In both syndromes, three types of molecular alterations have been reported: uniparental disomy 14, deletions and epimutations. In contrast to uniparental disomy and epimutations, deletions affecting regulatory elements in 14q32 are associated with a high-recurrence risk. Based on two single deletion cases a functional hierarchy of the IG-DMR as a regulator for the methylation of the MEG3-DMR has been proposed. We have identified two novel deletions of maternal origin spanning the MEG3-DMR, but not the IG-DMR in patients with upd(14)pat syndrome, one de novo deletion of 165 kb and another deletion of 5.8 kb in two siblings. The 5.8 kb deletion was inherited from the phenotypically normal mother, who carries the deletion in a mosaic state on her paternal chromosome 14. The methylation at both DMRs was investigated by quantitative next generation bisulfite sequencing and revealed normal methylation patterns at the IG-DMR in all patients with the exception of certain CpG dinucleotides. Thus, we could confirm that deletions of the MEG3-DMR does not generally influence the methylation pattern of the IG-DMR, which strengthens the hypothesis of a hierarchical structure and distinct functional properties of the two DMRs.

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