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Genomic imprinting ensures the parent-specific expression of either the maternal or the paternal allele, by different epigenetic processes (DNA methylation and histone modifications) that confer parent-specific marks (imprints) in the paternal and maternal germline, respectively. Most protein-coding imprinted genes are involved in embryonic growth, development, and behavior. They are usually organized in genomic domains that are regulated by differentially methylated regions (DMRs). Genomic imprints are erased in the primordial germ cells and then reset in a gene-specific manner according to the sex of the germline. The imprinted genes regulate and interact with other genes, consistent with the existence of an imprinted gene network. Defects of genomic imprinting result in syndromal imprinting disorders. To date a dozen congenital imprinting disorders are known. Usually, a given imprinting disorder can be caused by different types of defects, including point mutations, deletions/duplications, uniparental disomy, and epimutations. Causative trans-acting factors in imprinting disorders, including ZFP57 and the subcortical maternal complex (SCMC), have the potential to affect multiple DMRs across the genome, resulting in a multi-locus imprinting disturbance. There is evidence that mutations in components of the SCMC can confer an increased risk for imprinting disorders.

Imprinting disorders are a group of rare diseases with a broad phenotypic spectrum caused by a wide variety of genetic and epigenetic disturbances of imprinted genes or gene clusters. The molecular genetic causes and their respective frequencies vary between the different imprinting disorders so that each has its unique requirements for the diagnostic workflow, making it challenging. To add even more complexity to this field, new molecular genetic causes have been identified over time and new technologies have enhanced the detectability e. g. of mosaic disturbances. The precise identification of the underlying molecular genetic cause is of utmost importance in regard to recurrence risk in the families, tumour risk, clinical management and conventional and in the future therapeutic managements. Here we give an overview of the imprinting disorders, their specific requirements for the diagnostic workup and the most common techniques used and point out possible pitfalls.

Imprinting disorders are exceptional within the group of monogenic syndromes. They are associated with molecular changes affecting imprinted regions and usually do not follow the rules of Mendelian inheritance. They account for a relevant proportion of congenital disorders, especially within the syndromal growth entities with endocrine, neurological, and skeletal characteristics. In patients with imprinting disorders and accelerated growth, significant tumor risks have to be considered. The number of known imprinting disorders increases with the identification of new regions in which parentally imprinted genes are located. Imprinting disorders are caused by genomic pathogenic variants affecting imprinted genes, as well as by aberrant imprinting marks (epimutations) in the patients themselves. Additionally, maternal effect mutations have recently been identified that trigger secondary epimutations in the offspring. These maternal effect mutations explain not only imprinting disorders in their children, but also recurrent reproductive failure in the families. This review aims to provide an overview of the recent findings in 13 well-known imprinting disorders relating to clinical diagnosis, management and counseling.

In imprinting disorders, where the active copy of an imprinted gene is mutated or lost, there is a unique opportunity for causal treatment by unsilencing the other, dormant allele. Depending on the mechanism by which the allele is silenced, unsilencing can be achieved by epigenetic drugs, antisense-oligonucleotides (ASOs) or epigenome editing. While most of the research is still preclinical, first-in-humans studies with ASOs have started in 2020.