Congenital imprinting disorders: EUCID.net - a network to decipher their aetiology and to improve the diagnostic and clinical care

Eggermann et al. Clinical Epigenetics (2015) 7:23 DOI 10.1186/s13148-015-0050-z REVIEW Open Access Congenital imprinting disorders: EUCID.net a network to decipher their aetiology and to improve the diagnostic and clinical care Thomas Eggermann1,13*, Irène Netchine2,3,4, I Karen Temple5, Zeynep Tümer6, David Monk7, Deborah Mackay5, Karin Grønskov6, Andrea Riccio8,9, Agnès Linglart10,11 and Eamonn R Maher12 Abstract Imprinting disorders (IDs) are a group of eight rare but probably underdiagnosed congenital diseases affecting growth, development and metabolism. They are caused by similar molecular changes affecting regulation, dosage or the genomic sequence of imprinted genes. Each ID is characterised by specific clinical features, and, as each appeared to be associated with specific imprinting defects, they have been widely regarded as separate entities. However, they share clinical characteristics and can show overlapping molecular alterations. Nevertheless, IDs are usually studied separately despite their common underlying (epi)genetic aetiologies, and their basic pathogenesis and long-term clinical consequences remain largely unknown. Efforts to elucidate the aetiology of IDs are currently fragmented across Europe, and standardisation of diagnostic and clinical management is lacking. The new consortium EUCID.net (European network of congenital imprinting disorders) now aims to promote better clinical care and scientific investigation of imprinting disorders by establishing a concerted multidisciplinary alliance of clinicians, researchers, patients and families. By encompassing all IDs and establishing a wide ranging and collaborative network, EUCID.net brings together a wide variety of expertise and interests to engender new collaborations and initiatives. Keywords: Imprinting disorders, Imprinted genes, Epimutation, Uniparental disomy, EUCID.net, Networking Review Introduction Imprinting disorders (IDs) are a group of eight rare congenital diseases affecting growth, development and metabolism with a lifelong impact on patients’ quality of life. They are caused by changes in gene regulation (‘epigenetic mutation’), gene dosage and - rarely - in gene or genomic sequences (‘genetic mutation’) (Figure 1). The term genomic imprinting describes the expression of specific genes in a parent-of-origin-specific manner - that is, they are expressed only from the maternal or from the paternal gene copy, but not biparentally (for review: [1]). The underlying epigenetic basis does not involve the DNA sequence itself, but regulatory mechanisms that ensure * Correspondence: 1 Department of Human Genetics, RWTH Aachen, Aachen 52074, Germany 13 Department of Human Genetics, University Hospital, RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany Full list of author information is available at the end of the article the transmission of specific gene expression patterns from one cell generation to another, ensuring the maintenance of cellular identity. So far, more than 60 human genes have been shown to be imprinted, but there are probably many more (for review: [2]). The normal imprinting marks are inherited from the parental gametes and are then maintained in the somatic cells of an individual. Their programming is subject to an imprinting cycle during life which leads to a reprogramming at each generation (for review: [3]): In early development, methylation of the mammalian genome is comprehensively remodelled, but imprinting marks are exempt from developmental reprogramming; instead, they are erased in the germ line and re-established according to the sex of the contributing parent for the next generation. Many genes regulated by genomic imprinting are found in clusters, that is, imprinted loci often comprise multiple genes under coordinated control. At the molecular level, the expression of genes within imprinted regions © 2015 Eggermann et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Eggermann et al. Clinical Epigenetics (2015) 7:23 Page 2 of 10 Figure 1 The four molecular mechanisms of IDs, resulting in a disturbed expression of imprinted genes. is influenced by specific patterns of DNA methylation, by changes in chromatin structure and by post-translational histone modifications, collectively designated as epigenetic regulation (for review: [4,5]). The epigenetic machinery is extremely complex and results in a unique transcriptional activity of different cells with identical DNA sequences. Indeed, this carefully orchestrated interplay is prone to various disturbances resulting in distinct pathological courses, for example, malignant tumours or - in the case of parentally imprinted genes - IDs. In IDs, the regulation of imprinted genes can be disturbed by four different molecular alterations: genomic imbalances (duplications/deletions), uniparental disomy (UPD; the inheritance of both homologos of a chromosomal pair from only one parent), epimutations (disturbed methylation) or point mutations in an imprinted gene. Whereas in the majority of ID patients, only the disease-specific loci are affected, an increasing number of ID patients are reported showing a disturbed methylation at multiple differentially methylated regions (DMRs), the so-called multilocus imprinting disturbances (MLID) (see below). The extreme examples of unbalanced imprinting patterns are genome-wide UPDs, that is, the whole genome is inherited only from the father or from the mother. In both cases, the resulting conception is not viable. However, mosaic genome-wide UPD has been reported to be compatible with life (for review: [6]). The known imprinting disorders Most patients with one of the currently established IDs are diagnosed in early childhood. In contrast, the diagnosis in the prenatal workup or puberty or adulthood is often hampered because the clinical spectrum is broad, and some features are subtle, overlapping and transient. As a result, some IDs are probably mis- and underdiagnosed. Each ID is characterised by specific clinical features, and as they appeared to be associated with specific imprinting defects, they have been regarded as separate entities. Indeed, the majority of IDs have some shared clinical characteristics (Table 1), that is: – prenatal and/or postnatal growth retardation or prenatal and postnatal overgrowth; – hypo- or hyperglycemia; – abnormal feeding behaviour in early childhood and later; and – behavioural difficulties in childhood. Imprinting disorder Alternative name/acronym Frequency OMIM Chromosomesa/ imprinted regions (...truncated)