Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences

Eggermann, Thomas, Yapici, Elzem, Bliek, Jet, Pereda, Arrate, Begemann, Matthias, Russo, Silvia, Tannorella, Pierpaola, Calzari, Luciano, de Nanclares, Guiomar Perez, Lombardi, Paola, Temple, I. Karen, Mackay, Deborah, Riccio, Andrea, Kagami, Masayo, Ogata, Tsutomu, Lapunzina, Pablo, Monk, David, Maher, Eamonn R. and Tümer, Zeynep (2022) Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences. Clinical Epigenetics, 14. ISSN 1868-7075

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Background: 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.

Item Type: Article
Additional Information: Funding Information: Open Access funding enabled and organized by Projekt DEAL. This work was funded by a grant from the Istituto de Salud Carlos III [Institute of Health Carlos III] of the Ministry of Economy and Competitiveness [Spain] (to GPdN and AP), co-financed by the European Regional Development Fund (PI20/00950) and the 2019 research unit grant from ESPE (to GdPN). EM is funded by the NIHR Cambridge Biomedical Research Centre, Rosetrees Trust; the University of Cambridge has received salary support (ERM.) from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. PL is funded by the Grant FIS 20/01053, ISCIII. AR is funded by AIRC grant IG 24405.
Uncontrolled Keywords: beckwith–wiedemann syndrome spectrum,differentially methylated regions,epimutations,gain of methylation,growth disturbances,imprinting disorders,loss of methylation,multi locus imprinting disturbance,silver–russell syndrome spectrum,transient neonatal diabetes mellitus,uniparental disomy,genetics(clinical),genetics,molecular biology,developmental biology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2716
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 23 Mar 2022 15:30
Last Modified: 22 Oct 2022 17:38
DOI: 10.1186/s13148-022-01259-x


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