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

Thomas Eggermann, Elzem Yapici, Jet Bliek, Arrate Pereda, Matthias Begemann, Silvia Russo, Pierpaola Tannorella, Luciano Calzari, Guiomar Perez de Nanclares, Paola Lombardi, I. Karen Temple, Deborah Mackay, Andrea Riccio, Masayo Kagami, Tsutomu Ogata, Pablo Lapunzina, David Monk, Eamonn R. Maher, Zeynep Tümer

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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.

Original languageEnglish
Article number41
JournalClinical epigenetics
Issue number1
Publication statusPublished - Dec 2022


  • 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

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