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Genomic imprinting disorders: lessons on how genome, epigenome and environment interact

Nature Reviews Geneticsvolume 20pages235248 (2019) | Download Citation


Genomic imprinting, the monoallelic and parent-of-origin-dependent expression of a subset of genes, is required for normal development, and its disruption leads to human disease. Imprinting defects can involve isolated or multilocus epigenetic changes that may have no evident genetic cause, or imprinting disruption can be traced back to alterations of cis-acting elements or trans-acting factors that control the establishment, maintenance and erasure of germline epigenetic imprints. Recent insights into the dynamics of the epigenome, including the effect of environmental factors, suggest that the developmental outcomes and heritability of imprinting disorders are influenced by interactions between the genome, the epigenome and the environment in germ cells and early embryos.

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The authors thank F. Cerrato, M. V. Cubellis and A. Sparago for careful reading of the manuscript. The authors apologize to all authors of studies that could not be cited owing to the concise nature of this Review. Individual authors thank the following funders for research support: Ministry of Education, Universities and Research, Research Projects of National Interest (MIUR PRIN) 2015 (JHLY35), Telethon-Italia (GGP15131 and AIRC IG18671) (A.R.); Deutsche Forschungsgemeinschaft (DFG) (EG110/15-1) (T.E.); Spanish Ministry of Economy and Competitiveness (MINECO; BFU2014-53093-R and BFU2017-85571-R) co-funded with the European Union Regional Development Fund (FEDER) (D.M.). E.R.M. acknowledges support from National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and an NIHR Senior Investigator Award. The University of Cambridge has received salary support in respect of E.R.M. from the National Health Service (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 NIHR, NHS or Department of Health.

Reviewer information

Nature Reviews Genetics thanks Y.-H. Jiang and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

    • David Monk
  2. Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK

    • Deborah J. G. Mackay
  3. Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany

    • Thomas Eggermann
  4. Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK

    • Eamonn R. Maher
  5. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania ’Luigi Vanvitelli’, Caserta; Institute of Genetics and Biophysics ’Adriano Buzzati–Traverso’ CNR, Napoli, Italy

    • Andrea Riccio


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The authors contributed equally to all aspects of the article.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Andrea Riccio.

Supplementary information


Genomic imprinting

The epigenetic marking of a gene on the basis of parental origin that results in monoallelic expression.


Epigenetic profiles that are maintained in somatic tissues, resulting in interindividual variation.

Imprinting disorders

Diseases associated with disruption of imprinted gene expression that can be caused by genetic or epigenetic defects.

Uniparental disomy

(UPD). A genetic defect characterized by the presence of two copies of a chromosome or part of the chromosome derived from only one parent.


With reference to imprinting disorders, epigenetic changes that affect the regulation of imprinted loci. An epimutation is primary if there is no detectable genetic cause and secondary if it is associated with a genetic cause.

cis-acting elements

DNA sequences that regulate the expression of a gene that is present on the same chromosome.

trans-acting factors

Proteins that regulate the expression of a gene.

Epigenetic reprogramming

The erasure of pre-existing epigenetic marks that enable subsequent remodelling of chromatin.


The chromatin modifications influencing genome function but not involving the underlying DNA sequence that can be propagated through cell division.

Imprinting centre

Also known as imprinting control region. A functional definition of germline differentially methylated regions (gDMRs) that have been shown through either genetic targeting in mice or mutations in humans to regulate imprinted gene expression. Not all gDMRs have been shown to be imprinting centres.

Germline differentially methylated region

(gDMR). A region of differential DNA methylation between the parental alleles in somatic cells that originates from the gametes. gDMRs that survive embryonic reprogramming are generally associated with imprinted genes.

Loss of methylation

(LOM). With reference to imprinting disorders, loss of differential imprinting centre methylation detected in individuals that causes deregulation of imprinted genes in the domain controlled by the imprinting centre.

Gain of methylation

(GOM). With reference to imprinting disorders, gain of methylation on the unmethylated allele of the imprinting centre. It is detected in people and causes deregulation of imprinted genes in the domain controlled by the imprinting centre.

Secondary DMRs

Also known as somatic differentially methylated regions (DMRs). Regions of differential DNA methylation between parental alleles that do not originate in the germ line. They are regulated in a hierarchical fashion by a nearby imprinting centre region.

Multilocus imprinting disturbances

(MLIDs). Methylation anomalies at imprinted differentially methylated regions in individuals with imprinting disorders in addition to those that are normally associated with disease.


A fertilized ovum before the first cell division that represents the earliest stage of embryonic development. The genome of the zygote is a combination of the DNA in each gamete.

Primordial germ cells

(PGCs). Stem cell-like cells found in the gonadal ridge of developing embryos that develop into gametes following sex-specific epigenetic reprogramming and meiosis.


The developmental stage of a mammalian embryo just before implantation, consisting of an inner cell mass, which will form the embryo, and a cavity with an outer layer called trophoblast, which gives rise to the placenta.

Genome activation

The initiation of gene expression in the developing embryo. The initial burst of expression is termed zygotic genome activation and is regulated by pioneer transcription factors during the oocyte-to-embryo transition. Initiation of expression in cleavage embryos is referred to as embryonic genome activation.


The haploid nucleus from a male or female gamete before the genetic material fuse at syngamy.

Maternal-effect gene

A gene coding for an oocyte-derived transcript or protein that is required for the early development of the embryo.

Hydatidiform mole

A benign gestational trophoblastic disease developing during pregnancy and resulting from abnormal fertilization. It is characterized by trophoblastic proliferation and little or no embryonic tissue. It is commonly sporadic and contains only sperm DNA. Occasionally, it can be biparental, recurrent and familial, following an autosomal recessive mode of inheritance.


The proportion of individuals in a population with a specific genotype who show an associated phenotypic trait. Incomplete penetrance occurs when not all individuals carrying a dominant deleterious genetic variant express the associated clinical phenotype.

Subcortical maternal complex

(SCMC). A large multiprotein complex comprising NLRP5, OOEP, TLE6, PADI6 and KHDC3L that localizes to the outermost regions of the cytoplasm in oocytes and is excluded from regions of cell-to-cell contact in cleavage embryos.

Endogenous retroviruses

Also known as retrotransposons. Repetitive genetic elements present in the genome that, similarly to retroviruses, use the activity of reverse transcriptase to move from one locus to another.


Basic proteins that largely replace histones in the nucleus of mature sperm for more condensed DNA packaging.


A situation in which one-half of the normal level of a gene product, usually as a consequence of a loss-of-function mutation, is not sufficient for normal function.


A phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age or with greater severity in succeeding generations.

Assisted reproductive technologies

(ART). Techniques used to achieve pregnancy during the treatment of infertility. ARTs cover a wide spectrum of treatments including the use of fertility drugs, intrauterine insemination and in vitro fertilization and/or intracytoplasmic sperm injection.

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