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

doi:10.1186/s13148-022-01259-x

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

Aston Medical School

Rheinisch-Westfälische Technische Hochschule Aachen
Rheinische Friedrich-Wilhelms-Universität Bonn
Bioaraba Health Research Institute
Research Laboratory of Medical Cytogenetics and Molecular Genetics
University Hospital Southampton
University Hospital Southampton NHS Foundation Trust
University of Campania ‘Luigi Vanvitelli’ Caserta Italy
National Research Institute for Child Health and Development
Hamamatsu Medical Center
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
University of East Anglia
Department of PKU, Copenhagen University Hospital, Denmark.

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46 Citations (SciVal)

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Abstract

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 language	English
Article number	41
Number of pages	17
Journal	Clinical epigenetics
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s13148-022-01259-x
Publication status	Published - 16 Mar 2022

Bibliographical note

Copyright © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Funding

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 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. PL is funded by the Grant FIS 20/01053, ISCIII. AR is funded by AIRC grant IG 24405.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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

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10.1186/s13148-022-01259-xLicence: CC BY 4.0

T Eggermann et al_Trans-acting genetic variants cuasing multilocus imprinting disturbance MLID
Copyright © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Final published version, 1.25 MBLicence: CC BY 4.0

Cite this

Eggermann, T., Yapici, E., Bliek, J., Pereda, A., Begemann, M., Russo, S., Tannorella, P., Calzari, L., de Nanclares, G. P., Lombardi, P., Temple, I. K., Mackay, D., Riccio, A., Kagami, M., Ogata, T., Lapunzina, P., Monk, D., Maher, E. R., & Tümer, Z. (2022). Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences. Clinical epigenetics, 14(1), Article 41. https://doi.org/10.1186/s13148-022-01259-x

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Eggermann, T, Yapici, E, Bliek, J, Pereda, A, Begemann, M, Russo, S, Tannorella, P, Calzari, L, de Nanclares, GP, Lombardi, P, Temple, IK, Mackay, D, Riccio, A, Kagami, M, Ogata, T, Lapunzina, P, Monk, D, Maher, ER & Tümer, Z 2022, 'Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences', Clinical epigenetics, vol. 14, no. 1, 41. https://doi.org/10.1186/s13148-022-01259-x

TY - JOUR

T1 - Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences

AU - Eggermann, Thomas

AU - Yapici, Elzem

AU - Bliek, Jet

AU - Pereda, Arrate

AU - Begemann, Matthias

AU - Russo, Silvia

AU - Tannorella, Pierpaola

AU - Calzari, Luciano

AU - de Nanclares, Guiomar Perez

AU - Lombardi, Paola

AU - Temple, I. Karen

AU - Mackay, Deborah

AU - Riccio, Andrea

AU - Kagami, Masayo

AU - Ogata, Tsutomu

AU - Lapunzina, Pablo

AU - Monk, David

AU - Maher, Eamonn R.

AU - Tümer, Zeynep

N1 - Copyright © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

PY - 2022/3/16

Y1 - 2022/3/16

N2 - 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.

AB - 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.

KW - Inprinting disorders

KW - Differentially methylated regions

KW - Multi locus imprinting disturbance

KW - Uniparental disomy

KW - Growth disturbances

KW - Epimutations

KW - Loss of methylation

KW - Gain of methylation

KW - Beckwith-Wiedemann syndrome spectrum

KW - Silver-Russell syndrome spectrum

KW - Transient neonatal diabetes mellitus

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U2 - 10.1186/s13148-022-01259-x

DO - 10.1186/s13148-022-01259-x

M3 - Article

C2 - 35296332

SN - 1868-7075

VL - 14

JO - Clinical epigenetics

JF - Clinical epigenetics

IS - 1

M1 - 41

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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