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dc.contributor.authorEggermann, Thomas
dc.contributor.authorYapici, Elzem
dc.contributor.authorBliek, Jet
dc.contributor.authorPereda, Arrate
dc.contributor.authorBegemann, Matthias
dc.contributor.authorRusso, Silvia
dc.contributor.authorTannorella, Pierpaola
dc.contributor.authorCalzari, Luciano
dc.contributor.authorde Nanclares, Guiomar Perez
dc.contributor.authorLombardi, Paola
dc.contributor.authorTemple, I Karen
dc.contributor.authorMackay, Deborah
dc.contributor.authorRiccio, Andrea
dc.contributor.authorKagami, Masayo
dc.contributor.authorOgata, Tsutomu
dc.contributor.authorLapunzina, Pablo
dc.contributor.authorMonk, David
dc.contributor.authorMaher, Eamonn R
dc.contributor.authorTümer, Zeynep
dc.description.abstractBACKGROUND: Imprinting disorders are a group of congenital diseases which are characterized by molecular alterations affecting differentially methylated regions (DMRs). To date, at least twelve imprinting disorders have been defined with overlapping but variable clinical features including growth and metabolic disturbances, cognitive dysfunction, abdominal wall defects and asymmetry. In general, a single specific DMR is affected in an individual with a given imprinting disorder, but there are a growing number of reports on individuals with so-called multilocus imprinting disturbances (MLID), where aberrant imprinting marks (most commonly loss of methylation) occur at multiple DMRs. However, as the literature is fragmented, we reviewed the molecular and clinical data of 55 previously reported or newly identified MLID families with putative pathogenic variants in maternal effect genes (NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6) and in other candidate genes (ZFP57, ARID4A, ZAR1, UHRF1, ZNF445). RESULTS: In 55 families, a total of 68 different candidate pathogenic variants were identified (7 in NLRP2, 16 in NLRP5, 7 in NLRP7, 17 in PADI6, 15 in ZFP57, and a single variant in each of the genes ARID4A, ZAR1, OOEP, UHRF1, KHDC3L and ZNF445). Clinical diagnoses of affected offspring included Beckwith-Wiedemann syndrome spectrum, Silver-Russell syndrome spectrum, transient neonatal diabetes mellitus, or they were suspected for an imprinting disorder (undiagnosed). Some families had recurrent pregnancy loss. CONCLUSIONS: Genomic maternal effect and foetal variants causing MLID allow insights into the mechanisms behind the imprinting cycle of life, and the spatial and temporal function of the different factors involved in oocyte maturation and early development. Further basic research together with identification of new MLID families will enable a better understanding of the link between the different reproductive issues such as recurrent miscarriages and preeclampsia in maternal effect variant carriers/families and aneuploidy and the MLID observed in the offsprings. The current knowledge can already be employed in reproductive and genetic counselling in specific situations.
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.sourcenlmid: 101516977
dc.sourceessn: 1868-7083
dc.subjectBeckwith–Wiedemann syndrome spectrum
dc.subjectDifferentially methylated regions
dc.subjectGain of methylation
dc.subjectGrowth disturbances
dc.subjectImprinting disorders
dc.subjectLoss of methylation
dc.subjectMulti locus imprinting disturbance
dc.subjectSilver–Russell syndrome spectrum
dc.subjectTransient neonatal diabetes mellitus
dc.subjectUniparental disomy
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectBeckwith-Wiedemann Syndrome
dc.subjectCCAAT-Enhancer-Binding Proteins
dc.subjectDNA Methylation
dc.subjectGenomic Imprinting
dc.subjectMaternal Inheritance
dc.subjectSilver-Russell Syndrome
dc.subjectUbiquitin-Protein Ligases
dc.titleTrans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences.
prism.publicationNameClin Epigenetics
dc.contributor.orcidEggermann, Thomas [0000-0002-8419-0264]
pubs.funder-project-idInstituto de Salud Carlos III (PI20/00950, FIS 20/01053)

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International