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


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.

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Divisions: College of Health & Life Sciences > Aston Medical School
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 Car- los III] of the Ministry of Economy and Competitiveness [Spain] (to GPdN and AP), co-financed by the
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Uncontrolled Keywords: Inprinting disorders,Differentially methylated regions,Multi locus imprinting disturbance,Uniparental disomy,Growth disturbances,Epimutations,Loss of methylation,Gain of methylation,Beckwith-Wiedemann syndrome spectrum,Silver-Russell syndrome spectrum,Transient neonatal diabetes mellitus
Publication ISSN: 1868-7083
Last Modified: 11 Jul 2024 07:26
Date Deposited: 04 Jan 2024 17:19
Full Text Link:
Related URLs: https://clinica ... 148-022-01259-x (Publisher URL)
PURE Output Type: Article
Published Date: 2022-03-16
Accepted Date: 2022-02-28
Authors: 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.
Tümer, Zeynep



Version: Published Version

License: Creative Commons Attribution

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