Eggermann et al.

Clinical Epigenetics (2015) 7:123

DOI 10.1186/s13148-015-0143-8

REVIEW Open Access

Imprinting disorders: a group of congenital

disorders with overlapping patterns of
molecular changes affecting imprinted loci
Thomas Eggermann1,13,14*, Guiomar Perez de Nanclares2, Eamonn R. Maher3, I. Karen Temple4,5, Zeynep Tümer6,
David Monk7, Deborah J. G. Mackay4,5, Karen Grønskov6, Andrea Riccio8, Agnès Linglart9 and Irène Netchine10,11,12

Abstract
Congenital imprinting disorders (IDs) are characterised by molecular changes affecting imprinted chromosomal
regions and genes, i.e. genes that are expressed in a parent-of-origin specific manner. Recent years have seen a
great expansion in the range of alterations in regulation, dosage or DNA sequence shown to disturb imprinted
gene expression, and the correspondingly broad range of resultant clinical syndromes. At the same time, however,
it has become clear that this diversity of IDs has common underlying principles, not only in shared molecular
mechanisms, but also in interrelated clinical impacts upon growth, development and metabolism. Thus, detailed
and systematic analysis of IDs can not only identify unifying principles of molecular epigenetics in health and
disease, but also support personalisation of diagnosis and management for individual patients and families.
Keywords: Imprinting disorders, Imprinted genes, Epimutation, Uniparental disomy

Background by successive removal and re-establishment in the germ

Imprinting disorders (IDs) are a group of congenital dis- cell lineages, and then in early zygotic development. The
eases characterised by overlapping clinical features af- critical difference between imprinting marks and all
fecting growth, development and metabolism, and others is that they elude postzygotic reprogramming,
common molecular disturbances, affecting genomically and therefore are essentially ubiquitous and permanent
imprinted chromosomal regions and genes. The term in somatic tissues - except for the germline lineage that
genomic imprinting describes the expression of specific embarks upon the establishment of the subsequent gen-
genes in a parent-of-origin specific manner - i.e. they are eration (for review, [1]).
expressed only from the maternal or from the paternal Imprinted loci often comprise multiple genes under
gene copy, but not biparentally. Disturbances of coordinated epigenetic control (Figs. 1, 2, 3, 4, 5, 6, 7, 8
imprinted genes may alter their regulation (“epigenetic and 9). This control includes four interacting molecular
mutation") and dosage and rarely their genomic se- components: DNA methylation, post-translational his-
quences can be altered (“genetic mutation”). tone modification, chromatin structure and non-coding
So far, more than 150 human genes have been shown RNAs. The intricate interactions of these regulatory
to be imprinted (for review, http://www.geneimprint.- mechanisms across development lead to a stage- and
com/site/genes-by-species), but it is likely that more re- tissue-specific transcriptional activity in cells with identi-
main to be identified. Imprinting marks, like other cal DNA sequences.
epigenetic marks, are re-established at each generation In IDs, the regulation of imprinted genes and imprint-
ing clusters are disturbed by different changes. In the
majority of ID patients only the disease-specific loci are
* Correspondence: teggermann@ukaachen.de
1
Department of Human Genetics, RWTH Aachen, Pauwelsstr. 30, Aachen,
affected, but an increasing number of individuals have
Germany been shown to have disturbed methylation at multiple
13
Sorbonne Universites, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, imprinted loci, the so-called multilocus methylation im-
Paris, France
Full list of author information is available at the end of the article
printing disturbances (MLID). Another extreme example

© 2015 Eggermann et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 2 of 18

Fig. 1 PLAGL1 imprinted region on chromosome 6q24, altered in TNDM. The currently known imprinted loci associated with one of the known
IDs. (Filled boxes, protein coding genes; empty boxes, non-coding genes; Ω miRNAs; filled lollipops, methylated regions; empty lollipops,
unmethylated regions; black, genes with biparental expression; red, genes expressed from the maternal (mat) chromosome; blue, genes expressed
from the paternal (pat) chromosome; grey, silenced gene copies. Arrows above the genes, transcription direction of sense genes; arrows below
the genes, transcription direction of anti-sense genes. IC, imprinting control region)

of unbalanced imprinting patterns is uniparental dip- Since the genetic counseling for each ID is affected by
loidy (e.g. complete hydatidiform moles, where all the both its familial inheritance and its underlying pathogen-
chromosomes are of paternal origin) or triploidies (e.g. etic mechanism, precise molecular diagnosis is essential
partial hydatidiform moles where an extra haploid set of for accurate management and reproductive counseling.
chromosomes of either maternal or paternal origin is Furthermore, in some IDs somatic and germline mosai-
present). These cases are not viable. However, mosaic cism have been reported, a finding which may be diffi-
genomewide uniparental isodiploidy has been reported cult to diagnose, but must be considered since it may
to be compatible with life (for review, [2]). compromise molecular genetic testing.

Types of mutations and epimutations in IDs Uniparental Disomy (UPD)

In the majority of the well established IDs, the same four UPD is the inheritance of both chromosomal homo-
classes of molecular changes have been reported (Table 1, logues from the same parent and has been reported for
Figs. 1, 2, 3, 4, 5, 6, 7, 8 and 9): uniparental disomy nearly all IDs (Table 1; for review, [3]). The recurrence
(UPD), chromosomal imbalances, aberrant methylation risk for another child with UPD is generally low with the
(epimutation) and genomic mutations in imprinted exception of those UPDs affecting acrocentric chromo-
genes. The functional result in each case is the unbal- somes (chromosomes 14 and 15): these chromosomes
anced expression of imprinted genes, but the phenotypic are prone to Robertsonian translocations (RT) which
outcome depends on the parental allele affected by the predispose to non-disjunctional errors and thus a UPD
mutation. formation. However, the risk to have a child with UPD is

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 3 of 18

Fig. 2 The loci GRB10 in 7p12.1 and MEST in 7q32, affected by (segmental) upd(7)mat or chromosomal imbalances in SRS

below 1 %, but prenatal testing for UPD is recom- Intragenic mutations in imprinted genes
mended in carriers of balanced translocations affecting So far, genomic point mutations in imprinted genes have
chromosomes carrying imprinted genes [4]. only been reported for Beckwith-Wiedemann syndrome
(BWS), Silver-Russell syndrome (SRS), AS, precocious
Chromosomal rearrangements (deletions, duplications, puberty and pseudohypoparathyoridism (PHP) (Table 1).
translocations) In precocious puberty syndrome (central precocious pu-
Chromosomal imbalances either cause a loss of a gene berty 2; cppb2), MKRN3 mutations are the only causa-
and thereby a loss of expression of an imprinted gene in tive molecular alterations known so far. In the other
case of deletions or translocations or they result in an IDs, their significance differs: AS mutations in the
overexpression by duplication of imprinted chromo- UBE3A contribute to 10–15 % of cases, and approxi-
somal material. However, due to the complex regulation mately 30 % are inherited. In PHP, mutations on the
mechanisms in imprinted regions, loss of chromosomal coding maternal allele of GNAS are responsible for
material can also indirectly cause an overexpression of 70 % of type 1A disease (~50 % of total PHP), whereas,
an imprinted gene due to the removal of a negative cis- deletions of genomic regulatory regions have been iden-
acting element and vice versa (e.g. [5–7]). tified in 20–30 % of the 1B subtype (~8.5 % of total
In some IDs, deletions account for the majority of PHP) [8]. In BWS, inhibiting CDKN1C mutations can
cases, e.g. in Angelman syndrome (AS) and Prader- be detected, in SRS, only one case with an activating
Willi syndrome (PWS). They can either occur de novo, CDKN1C mutation has been reported so far [9]. To fur-
or they can be caused by inherited chromosomal rear- ther determine the recurrence risk in the families of
rangements (e.g. RT). In case of familial cases, the these patients, familial segregation studies should be of-
parent-of-origin-dependent gene expression results in fered to establish the maternal/paternal inheritance or
autosomal-dominant inheritance with a parent-of- lack thereof, even when parents do not show obvious
origin-dependant penetrance. clinical features.

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 4 of 18

Fig. 3 The 11p15.5 cluster can be divided in two functional domains whose imprinting is dependent on distinct imprinting control regions
(H19/IGF2: IG DMR and KCNQ1OT1: TSS DMR). Mainly hypomethylation of the KCNQ1OT1: TSS DMR is responsible for SRS

Epimutations point mutations in regulatory domains can affect the im-

Epimutations aberrant methylation of a differentially printing status of a DMR [6, 10, 14]. It is noteworthy that
methylated region (DMR) without alteration of the same some molecular changes may occur postzygotically, result-
genomic DNA sequence account for up to 50 % of mo- ing in a mosaic distribution. Mosaicism can obscure
lecular changes in IDs (Table 1). To contribute to the genotype-phenotype correlation and is also associated
full clinical picture of an ID, hypo- or hypermethylation with somatic asymmetry; and discordant monozygotic
should affect the disease-specific germ-line DMR (e.g. twinning, which can be regarded as an extreme expression
the H19-DMR in 11p15), but in several IDs the methyla- of epigenetic asymmetry, is a common feature in IDs (for
tion at further DMRs (e.g. IGF2-DMRs in 11p15) is review, [15]). It may also render difficult the molecular
altered [10] and might influence the severity of an ID diagnosis if the analysed tissue is not or poorly epigeneti-
(e.g. Kagami-Ogata syndrome/KOS14, [11]). Epimutation cally modified.
can occur as a result of a DNA mutation in a cis- or
trans-acting factor (“secondary epimutation”), or as a Clinical and molecular findings in Imprinting
primary epimutation in the absence of any DNA se- Disorders
quence change (“primary epimutation”). Primary epimu- With the exception of the precocious puberty syndrome,
tations often occur after fertilization and lead to somatic the clinical features of IDs are present at birth and in
mosaicism. It has been estimated that the rate of pri- early childhood. Indeed, some of them can be identified
mary epimutations is 1 or 2 orders of magnitude greater prenatally. Each ID is characterised by specific clinical
than somatic DNA mutations [12] and is associated with features, and they have been regarded as separate en-
assisted reproductive technology [13], in keeping with tities. However, the majority of IDs share clinical (and
environmental disturbances. molecular) characteristics (Tables 1 and 2), and in nearly
In terms of molecular mechanism, the four causes of all of them growth, metabolism and/or development are
IDs can interact: chromosomal translocations can pre- affected. Furthermore, they share several sequelae (e.g.
dispose to both imbalances and UPD, and deletions or diabetes; Table 2). In several disorders, the symptoms

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 5 of 18

Fig. 4 Epimutations and mutations in 11p15.5 are also responsible for BWS

are subtle, unspecific and transient; therefore, some IDs problems are rare and may be associated with MLID ra-
are probably mis- and underdiagnosed. ther than TNDM per se. Approximately 10 % of individ-
Currently, nine IDs have been described, but there are uals with TNDM1 do not present with hyperglycaemia
certainly more: In addition to the generally accepted at birth [19].
paediatric IDs and the specific precocious puberty entity, TNDM is associated with an overexpression of
there are three further molecular disturbances in discus- PLAGL1/ZAC in 6q24 (Fig. 1), a maternally imprinted
sion to represent separate IDs (upd(6)mat, upd(16)mat, gene. It encodes a zinc finger protein which binds DNA
upd(20)mat). and hence influences the expression of other genes (for
review, [20].
Transient neonatal diabetes mellitus type 1
Transient neonatal diabetes mellitus type type 1 Silver-Russell syndrome
(TNDM1) is characterised by intrauterine growth retard- SRS is a clinically and molecularly heterogeneous growth
ation (IUGR) and hyperglycaemia in infancy. The dia- retardation syndrome. Apart from pre- and postnatal
betes mellitus typically develops in the first weeks of life growth failure, the major features include a relative
and resolves by the age of 18 months; however, it is macrocephaly at birth, a typical facial gestalt (protruding
growing clear that individuals with TNDM are at risk of forehead, triangular face), body asymmetry, and feeding
relapse, in adolescence or early adulthood, with type 2 difficulties in infancy. Furthermore, first follow-up data
diabetes [16, 17]. Aside from these features, TNDM1 has indicate a risk for adult-onset diseases [21]. The clinical
no major cardinal features; however, individuals may presentation is variable and at least in part influenced by
have congenital abnormalities [18]. Macroglossia (large the mosaic distribution of molecular changes [22], but
tongue) affects just under half of infants with TNDM1, several scoring systems have been suggested [23]. Ap-
and about one in five individuals may also have a minor proximately 10 % of SRS patients have maternal UPD
anomaly of the abdominal wall. Other congenital for chromosome 7 (upd(7)mat) or segmental upd(7q)mat

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 6 of 18

Fig. 5 The imprinted region in 14q32.2, and changes associated with TS14

(for review, [24, 25]) (Fig. 2). The majority of patients loci, can be detected (including the ICR1 and
carry molecular changes in 11p15, the most prevalent KCNQ1OT1: TSS DMR DMRs)(for review, [34]). Most
(~40 %) being hypomethylation of H19/IGF2: IG DMR BWS cases are sporadic but familial inheritance is ob-
(Fig. 3). Additionally, numerous (submicroscopic) distur- served in up to 15 % of all cases. Microdeletions/dupli-
bances of chromosomes 7 and 11 as well as of other cations or point mutations at the ICRs are usually found
chromosomes have been described; thus screening for in familial BWS with aberrant 11p15 methylation; for ex-
cryptic genomic imbalances is indicated after exclusion ample, deletions and point mutations of OCT4/SOX4
of upd(7)mat and 11p15 epimutations [26, 27]. The binding sites in H19/IGF2: IG DMR are associated with
genes causing the SRS phenotype on chromosomes 7 H19/IGF2: IG DMR hypermethylation [5, 35, 36]. Con-
and 11 are currently unknown, but evidences for a role versely, CDKN1C mutations are frequent in familial
of IGF2 and CDKN1C in 11p15.5 and MEST in 7q32 cases with normal 11p15 methylation [37]. These BWS
have been reported [9, 28–30]. pedigrees resemble that of an autosomal dominant in-
heritance but with parent-of-origin dependent effects on
Beckwith-Wiedemann syndrome penetrance. Most cases of BWS with an KCNQ1OT1:
BWS was initially called EMG syndrome from its three TSS DMR epimutation are sporadic but there is an asso-
main features of exomphalos, macroglossia and (neo- ciation with assisted reproductive technologies [38]. Ro-
natal) gigantism. The clinical diagnosis of BWS is often bust genotype/epigenotype-phenotype correlations have
difficult due to its variable presentation and the pheno- been established for BWS [35, 39, 40]: hemihypertrophy
typic overlap with other overgrowth syndromes (for re- is strongly associated with upd(11)pat, exomphalos with
view, [31–33]) and isolated hemihypertrophy. In 5–7 % KCNQ1OT1: TSS DMR hypomethylation and CDKN1C
of children, embryonal tumours (most commonly Wilms mutations, and, most importantly, the risk of Wilms
tumour) are diagnosed. tumour is significantly increased in H19/IGF2: IG DMR
In nearly 80 % of BWS patients chromosome 11p15.5 hypermethylation and upd(11)pat in comparison to the
epimutations or mutations (Fig. 4), involving multiple other molecular subgroups. By contrast, other embryonic

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 7 of 18

Fig. 6 Molecular changes currently known to be associated with KOS14

tumors such as neuroblastoma and adrenal tumors are exclusion of the specific (epi)mutations. For TS14 the
observed in patients with KCNQ1OT1: TSS DMR or role of an altered RTL1 and DLK1 expression has been
upd(11)pat but at a much lower incidence. Hence, the de- suggested [42].
termination of the molecular subtype is important for an
individual prognosis and management. Nevertheless, the Kagami-Ogata syndrome
phenotypic transitions are fluid and testing for all molecu- The second recently defined ID is KOS14 which is
lar subtypes should be offered in patients with BWS mainly characterised by polyhydramnios, placentome-
features. galy, excessive birth weight, a unique facial appearance
with full cheeks and protruding philtrum, distinctive
Temple syndrome chest roentgenograms with coathanger rips and a bell-
Temple syndrome (TS14) was first described in 1991 in shaped thorax, abdominal wall defects (omphalocele,
a patient with a maternal UPD of chromosome 14 [41], diastasis recti), variable developmental delay and/or in-
and after it turned out that it is a recognizable pheno- tellectual disability, poor sucking usually requiring gas-
type the name upd(14)mat syndrome was suggested. tric tube feeding, hepatoblastoma and a mortality rate of
Meanwhile, other molecular changes have been reported 20–25 % in the neonate period [45].
as well [42, 43]; therefore, the name TS14 has been pro- Known causes of KOS are upd(14)pat (~65 %), epimu-
posed [44] (Fig. 5). TS14 is mainly characterised by pre- tations affecting the MEG3/DLK: IG DMR and the
natal and postnatal growth retardation, muscular MEG3: TSS DMR (~15 %) and microdeletions involving
hypotonia, feeding difficulties in early childhood, truncal the MEG3/DLK: IG DMR and/or the MEG3: TSS DMR
obesity and early onset of puberty. TS14 patients show (~20 %) (Fig. 6). The detailed characterisation of KOS14
clinical features overlapping with PWS and SRS; thus, with deletions of different sizes has allowed the deci-
screening for chromosome 14q32 should be performed phering of the regulation mechanism in the 14q32
in patients with PWS- and SRS-like phenotypes after imprinted region [11, 46]: whereas deletion of the

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 8 of 18

Fig. 7 The imprinted region in 15q11.2 and PWS. UBE3A encodes an E3 ubiquitin-protein ligase which is expressed exclusively from the maternal
allele in human fetal brain and in adult frontal cortex. The role of ATP10A is unclear

MEG3/DLK: IG DMR is associated with both the clinical considered. AS can be caused by maternally derived de
KOS14 phenotype and placental abnormalities, carriers novo deletion of 15q11-q13 (70–75 %), paternal unipa-
of deletions restricted to the MEG3: TSS DMR do not rental disomy (upd(15)pat) of chromosome 15 (3–7 %)
show placental abnormalities. It has been postulated that or an imprinting defect (2–3 %) all of which lead to lack
the increased expression of RTL1 is responsible for the of expression of maternally expressed 15q11-q13 genes
clinical outcome, whereas a role of DLK1 can be (Fig. 7). Furthermore, mutations in UBE3A also cause
neglected [42]. Angelman syndrome (10–15 %). Imprinting defects can
either be due to primary imprinting epimutations with-
Angelman syndrome out DNA sequence alterations or due to deletions in the
A clinical diagnosis of AS demands fulfilment of four imprinting centre (IC) critical region (AS-SRO) [48, 49].
major criteria and minimum three of the six minor cri- The 15q11-q13 chromosomal region contains imprinted
teria. The major criteria are severe developmental delay, genes, some of which are exclusively expressed from ei-
movement or balance disorder, severe limitations in ther of the parental alleles. Two exclusively maternally
speech and language and typical abnormal behavior in- expressed genes, UBE3A and ATP10A, are located with
cluding happy demeanor and excessive laughter. The six this region: UBE3A encodes an E3 ubiquitin-protein lig-
minor criteria are postnatal microcephaly, seizures, ab- ase which is expressed exclusively from the maternal al-
normal EEG, sleep disturbance, attraction to or fascin- lele in human foetal brain and in adult frontal cortex
ation with water, and drooling [47]. The unique clinical [50, 51]. AS can be caused either by lack of UBE3A ex-
features do not usually manifest within the first year of pression or by mutations in UBE3A. The role of the
life, but developmental delay is noticed around 6 months other imprinted gene, ATP10A, is however unclear. In
of age. In about 10 % of the individuals with a clinical individuals with deletions, UPD or imprinting defects,
diagnosis of AS it is not possible to find the underlying ATP10A expression is lacking, but in individuals with
genetic mechanism and other diagnoses should be point mutations in UBE3A it is left unaffected.

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 9 of 18

Fig. 8 Alterations in 15q11.2 in AS

Prader-Willi syndrome without DNA sequence alterations or it can be due to

PWS is clinically characterised by severe hypotonia and small deletions in the imprinting centre (IC) critical region
feeding difficulties in early infancy, followed by excessive (PWS-SRO) [54]. The 15q11-q13 chromosomal region
eating and development of morbid obesity in later in- contains imprinted genes, some of which are exclusively
fancy or early childhood. Cognitive impairment is seen expressed from either of the parental alleles. Paternally
in almost all individuals but varies in severity. A behav- expressed genes are: MKRN3, MAGEL2, NDN, PWRN1,
ioral phenotype with temper tantrums, stubbornness, C15orf2, SNURF-SNRPN and several snoRNA genes
manipulative behavior and obsessive-compulsive dis- (SNORD64, SNORD107, SNORD108, SNORD109A,
order is constant. Hypogonadism in both males and fe- SNORD109B, SNORD115 and SNORD116). SNORD115
males may cause genital hypoplasia and incomplete and SNORD116 are present in 47 and 24 gene copies, re-
pubertal development; and most individuals are infertile. spectively, whilst the other snoRNA genes are single copy
Short stature, and small hands and feet are common fea- genes. Deficiency of SNORD116 is thought to cause the
tures. Characteristic facial features, strabismus and scoli- key characteristics of the PWS phenotype [55, 56].
osis are often present. Clinical diagnostic criteria for
PWS have been developed [52, 53]; however, confirm- Precocious puberty
ation of the clinical diagnosis with molecular genetic Puberty is a complex biological process involving sexual
testing is required. maturation and accelerated growth. These processes nor-
PWS is caused by lack of expression of the paternally mally initiate when pulsatile secretion of gonadotropin-
contributed 15q11-q13 genes. There are three mecha- releasing hormone (GnRH) from the hypothalamus begins.
nisms leading to PWS: deletion of the 15q11-q13 Early activation of the hypothalamic-pituitary-gonadal axis
imprinted loci on the paternal allele (75–80 %), maternal results in gonadotropin-dependent precocious puberty
UPD of chromosome 15 (upd(15)mat) (20–25 %) and (also known as central precocious puberty, CPP; develop-
imprinting defects (<1 %) (Fig. 8). The common break- ment of secondary characteristics before the age of 8 year
point for the deletions are the same as for AS. Imprint- in girls and 9 years in boys). With the advent of advanced
ing defects can either be due to primary epimutations sequencing methods, exome-sequencing of familial cases

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 10 of 18

Fig. 9 Organization and imprinting of the complex GNAS locus at 20q13.22, causing PHP

of CPP have identified genetic defects in transcripts locus. PHP1A comprises patients affected with resistance
with no previous link to hypothalamic-pituitary-gonadal to PTH and TSH (and other GPCR proteins), and features
regulation. Loss-of-function mutations in the Makorin of obesity and Albright hereditary osteodystrophy includ-
ring finger 3 (MKRN3) were initially identified in CPP ing short stature, brachydactyly, ectopic ossifications and
families [57–60]. Consistent with the genes imprinting sta- mental retardation. PHP1A is caused by inactivating muta-
tus the phenotype was only present upon paternal trans- tions in the maternal allele of the GNAS gene. Paternal
mission of the mutation. Subsequently, mutations in GNAS mutations are associated with AHO, no hormonal
MKRN3 have been shown to be the most frequent cause resistance and no obesity, a constellation of features
of familial CPP and they have also been detected in nearly grouped under the term of pseudopseudohypoparathyroid-
4 % in a cohort of 215 non-familial idiopathic CCP [61]. ism (PPHP) as well as with progressive osseous heteropla-
The MKRN3 gene (also known as ZNF127) is an intron- sia (POH). In contrast, the phenotype of most PHP1B
less transcript located on chromosome 15q11.2 in the patients is limited to renal PTH resistance [62] and in
PWS critical region, encoding for a protein with C3H some cases, mild TSH resistance. Few patients with PHP1B
zinc-finger and RING zinc-finger motifs. Unlike other im- display some features of Albright hereditary osteodystro-
printing disorders that can result from multiple mecha- phy [63]. Patients with PHP1B share a loss of methylation
nisms, it is currently unknown if CCP can arise from loss at the A/B differentially methylated region (DMR) of
of MKRN3 expression due to deletion, segmental maternal GNAS, likely leading to the downregulated expression of
uniparental disomy or an imprinting defect. the GNAS-Gsα transcript in imprinted tissues (Fig. 9).
Some patients carry additional epigenomic changes along
Pseudohypoparathyroidism the GNAS locus. About 20 % of PHP1B are inherited and
PHP is a group of disorders characterised by PTH resist- due to deletions of GNAS imprinting control regions. The
ance in the kidney, i.e. pseudohypoparathyroidism. Most remaining 80 % are sporadic. A small subset is due to pa-
cases of PHP belong to the type 1, i.e. are caused by gen- ternal UPD of chromosome 20q, yet the vast majority are
etic or epigenetic alterations at the imprinted GNAS still of unknown cause (for review: [64]). Whilst obesity

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Table 1 Overview on the molecular findings in the currently known IDs and their clinical characteristics
Imprinting disorder Prevalence OMIM Chromosomes/ Type of mutation/epimutation and their MLID Mosaicism Recurrence risk Ma
imprinted regions frequencies
Transient Neonatal 1/300.000 601410 6q24: PLAGL1: alt-TSS upd(6)pat 40 % <1 % IUG
Diabetes Mellitus (TNDM) hyp
paternal duplications 40 % No Up to 50 %
keto
methylation defects 20 % ~50 % Yes <1 % om
Upd(6)mat Unknown Chromosome 6, upd(6)mat Yes Unknown
6q16.1qter
Silver-Russell syndrome 1/75.000- 180860 7 upd(7)mat ~10 % 1 No <1 % IUG
(SRS; Russell-Silver 1/100.000 casea calc
Syndrome, RSS) at b
11p15: upd(11p15)mat single case Unknown Rare
fore
Genome-wide uniparental single case Yes Rare diff
diploidy
maternal duplication <1 % No Up to 50 %
H19/IGF2: IG DMR hypomethylation >38 %a 7- Yes <1 %
10 %
CDKN1C point mutations 1 family reported No In familial cases: up
to 50 % in case of
maternal transmission
IGF2 point mutations 1 family reported No
Beckwith-Wiedemann 1/15.000 130650 11p15: upd(11p15)pat ~20 % Yes <1 % Pre
syndrome (BWS; org
Wiedemann-Beckwith Genome-wide uniparental ~2 % Yes <1 % om
syndrome, EMG) diploidy hyp
chromosomal aberrations 2-4 % No Up to 50 % incr
IH19/IGF2: hypermethylation 5-10 % Yes unclear
IG DMR; KCNQ1OT1:
TSS-DMR
hypomethylation 40-50 % 25 % Yes <1 %
CDKN1C point mutations 5 % (sporadic) No Up to 50 %
40–50 % (families)
Kagami-Ogata syndrome unknown 608149 14q32: upd(14)pat 65 % in case of RT IUG
(KOS14; upd(14)pat and
syndrome) MEG3/DLK1: IG DMR maternal deletion 15 % up to 50 % sha
MEG3: TSS DMR aberrant methylation 20 % <1 %
Temple syndrome (TS14; unknown 616222 14q32: upd(14)mat 78 % In case of RT IUG
upd(14)mat syndrome) feed
MEG3/DLK1: IG DMR paternal deletion 10 % Up to 50 %
obe
MEG3: TSS DMR aberrant methylation 12 % 1 <1 % sma
casea
Prader-Willi syndrome 1/25.000- 176270 15q11-q13 paternal deletion 70 % Up to 50 % PNG
(PWS) 1/10.000 hyp
upd(15)mat <30 % In case of RT

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 Eggermann et al. Clinical Epigenetics (2015) 7:123
Table 1 Overview on the molecular findings in the currently known IDs and their clinical characteristics (Continued)
aberrant methylation ~1 % 1 case <1 % hypopigmentation, obesity/
hyperphagia
Angelman syndrome 1/20.000- 105830 15q11-q13: maternal deletion 70 % No Up to 50 % mental retardation, microcephaly,
(AS) 1/12.000 no speech, unmotivated laughing,
upd(15)pat 1-3 % In case of RT ataxia, seizures, scoliosis
aberrant methylation ~4 % Yes <1 %
UBE3A point mutations 10-15 % No In familial cases: up
to 50 % in case of
maternal transmission
Precocious puberty Unknown 614356 15q11.2: MKRN3 point mutations 100 % No In familial cases: up Early activation of the hypothalamic-
(central precocious to 50 % in case of pituitary-gonadal axis results in
puberty 2; cppb2) paternal transmission gonadotropin-dependent precocious
puberty
Upd(16)mat Unknown Chromosome 16 upd(16)mat, often Yes <1 % IUGR (40-85 %); heterogeneous, but
associated with no specific or unique symptoms
chromosomal aberrations
Pseudohypo- unknown 603233 20q13: Maternally inherited 8.5 % Up to 50 % in case of Resistance to PTH and other
parathyroidism (PHP1B, deletions causing maternal transmission hormones; Albright hereditary
PHP1C, PHP1A) aberrant methylation osteodystrophy, subcutaneous
ossifications, feeding behaviour
612462 GNAS isolated epimutations 42.5 % 12.5 % <1 % anomalies, abnormal growth
103580 upd(20)pat 2.5 % 12.5 % <1 % patterns
maternal and paternal 46.5 % No Up to 50 % in case of
heterozygous loss of maternal transmission
function mutations in
GNAS coding sequence
Upd(20)mat syndrome unknown Chromosome 20 upd(20)mat No <1 % IUGR, PNGR, feeding difficulties
IUGR intrauterine growth retardation, PNGR postnatal growth retardation
a
This case carries both upd(7)mat and a TS14 epimutation [82], if studied in different tissues

Page 12 of 18
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 Eggermann et al. Clinical Epigenetics (2015) 7:123
Table 2 Comparison of the major clinical findings in the known and suggested IDs, showing a broad clinical overlap between the different disorders
Congenital ID TNDM upd(6)mat SRS BWS TS14 KOS14 PWS AS Precocious upd(16)mat PHP upd(20)mat
puberty
Reference [18] Weba [83] [33] [43] [84] [52] [85] [61] Weba [86] [70]
number of 155 13 20 44 403 51 34 90 61 63 15
patients
ID specific 6 6 7 11 11 14 14 15 15 15 16 20 20
chromosome
clinical BWS SRS upd(6)mat, TS14, TNDM, KOS14 SRS, PWS BWS TS14 AS infant SRS, SRS,
overlapwith upd(16)mat, upd(6)mat, upd(6)mat,
upd(20)mat upd(20)mat upd(16)mat
Major clinical
and overlapping
findings
IUGR Yes 53.8 % (7/13) 70 % 82 % 87 % 1 Rare No 77 % (47/61) 100 %
prenatal Yes 58.8 % (20/34) No Yes
overgrowth
placenta Abnormality: 8 % Abnormality: 35 % Placentomegaly Placentomegaly No
polyhydramion Reported 97 % (33/34) No
PNGR Yes 33.3 % (2/6) 65 % 57 % 79 % 36.6 % (11/30) 63 % No 2 % (1/49) 100 %
overgrowth Yes (6.7 % (2/30) No
organomegaly 43.8 % (153/349) No
Asymmetry 30 % 68 % 33.3 % (126/378 4% No
macroglossia 44 % (54/123) 94 % (379/403) No 7%
(3/35)
relative 90 % 70 % 56 % No 1 case
macrocephaly
relative 1 case >80 %
microcephaly
hypotonia 45 % (n = 143) [87] 93 % 88 % <80 % 1 case
abdominal wall 21 % (24/114) 1 case Rare 62.3 % (250/401) Omphalocele: No 1 case
defects 32.3 % (11(34)
Exomphalos: diastasis recti:
56.8 % (142/250) 67.6 % (23/34)
glycemic TNDM: 100 % Hypoglycemia: Hypoglycemia: Hypoglycemia: Hypoglycemia Diabetes no
disorder 24 % 19 %; diabetes 43.4 % (162/373) diabetes type type 2: 25 %
type 2 reported 2 reported in
in later life later life

Page 13 of 18
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 Eggermann et al. Clinical Epigenetics (2015) 7:123
Table 2 Comparison of the major clinical findings in the known and suggested IDs, showing a broad clinical overlap between the different disorders (Continued)
precocious Frequent Frequent Reported 86 % 4 % [88] No 100 %
puberty
mental Global delay: Global delay: 20 % 39 % 100 % 100 % 3%
retardation 65 %
speech delay 50 % 39 % No
speech
motor delay 50 % (7/14) 76 % (26/34) 100 %
learning 100 % 33 %
difficulties
behaviour 20 % 9% 70-90 % 100 % 9%
feeding 90 % 84 % Reported 43 % 78 % >80 % 7 cases
difficulties
seizures 1 case >80 % 1 case
excessive 75 % 64 % Increased
sweating sensitivity
to heat
scoliosis 5% 9% 23 % 40-80 % [88] <80 % 1 case
adipositas Reported in yes 67 % <80 %
later life [21]
dysmorphic/ 18 % (21/114) Triangular face 100 % >80 % 14.2 % Mild
typical facial (6/49)
gestalt
clinodactyly/ 8 % (9/116) 45 % 75 % 5 cases
finger
abnormalities
ear abnormalities Low set Low set posterior 61.8 % (230/372)
posterior
otitis media 20 % 14 % 17.6 % (9/51)
hepatoblastoma Reported Reported
cardiac 9 % (10/114) 9% 5-10 % [39]
anomalities
a
See http://www.fish.uniklinikum-jena.de/UPD.html (15.06.2015)

Page 14 of 18
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with molecular changes in disease-specific loci. However, somy of chromosome 20. All patients with upd(20)mat
three further clinical entities have been suggested in had intrauterine and postnatal growth retardation, and
which imprinted genes are known or suspected to be in- prominent feeding difficulties with failure to thrive
volved, and which might become IDs. often requiring gastric tube feeding in the first few
years of life. No dysmorphisms or congenital abnormal-
Maternal uniparental disomy of chromosome 6 ities or major developmental delay have been reported.
(upd(6)mat) So far, other types of molecular alterations have not yet
Maternal UPD of chromosome 6 (upd(6)mat) has been been reported, and a candidate region on chromosome
hypothesized to be associated with intrauterine growth 20 has not yet been defined. It is striking that these pa-
retardation: among the 13 cases reported so far, 7 re- tients have not been described to have features reminis-
vealed a IUGR (http://www.fish.uniklinikum-jena.de/ cent of paternal GNAS loss of function mutations,
UPD.html). Indeed, homozygosity of a recessive allele although the loss of the paternal GNAS allele (on chromo-
causing IUGR has been discussed as the pathogenic some 20) is associated with pre- and postnatal growth de-
mechanism as many patients share an isodisomic region fect and Albright hereditary osteodystrophy [8]. However,
in 6q16qter. However, not all upd(6)mat carriers pre- upd(20)mat probably presents a new imprinting disorder
senting IUGR share this region, in one case homozygosity and its identification requires specialized molecular
of a recessive CUL7 has been identified causing 3 M testing, which should be performed in patients with
syndrome, a growth retardation syndrome. However, it early-onset idiopathic isolated growth failure. In par-
has been postulated that upd(6)mat might be regarded as ticular patients with a clinical diagnosis of SRS or
a further imprinting disorder [67]. TS14, but exclusion of their known molecular distur-
bances, are strong candidates for upd(20)mat as there
Maternal uniparental disomy of chromosome 16 appears to be significant phenotypic overlap.
(upd(16)mat)
Maternal UPD of chromosome 16 (upd(16)mat) is the Multi-locus imprinting disturbances and the
most often reported UPD other than upd(15). This is “imprinted gene network”
not surprising since risk of UPD is much higher in chro- The clinical and molecular overlap between IDs suggests
mosomes involved in aneuploidies and trisomy 16 is the that there may be causal links between them, either by
most common autosomal trisomy in human abortions. shared causes of dysregulation affecting multiple imprinted
Trisomy 16 itself is usually lethal in non-mosaic state in genes, or by perturbation of interactions between the prod-
the fetus, but in trisomy rescue is compatible with life. As ucts of imprinted genes.
a consequence of UPD formation by trisomy rescue, many A growing number of ID patients have been reported
of the reported upd(16)mat cases are associated with tri- to exhibit multilocus imprinting disturbance or MLID
somy 16 mosaicism in the placenta (for review, http:// which can vary depending on the tissues studied [22, 71]
www.fish.uniklinikum-jena.de/UPD.html). The upd(16)mat (Table 1). Whilst the mechanisms associated with MLID
has been suspected to have clinical consequences. How- are currently unknown, they all present with underlying
ever, the heterogeneity of the birth defects observed sug- aberrations in allelic DNA methylation. Indeed, evi-
gested that the phenotype might rather be influenced by dence is growing that genomic mutations are involved
placenta insufficiency than by the UPD itself [68]. The pos- in the etiology of MLID; known trans-acting factors
sibility that upd(16)mat is associated with imprinting is dif- include mutations in the ZFP57, the NLRP2 or the
ficult to assess due to the trisomy 16 mosaicism present NLRP7 genes [72–75].
in many cases. By an extensive clinical analysis of a Another hypothesis which explains the clinical and
series of mosaic trisomy 16 cases (n = 83) including molecular overlap between the different IDs is the
upd(16)mat (n = 33), Yong et al. [69] concluded that “imprinted gene network” (IGN) [76]. The existence of
upd(16)mat might be associated with more severe the IGN has been based on the observation of co-
growth retardation in utero and an elevated risk of expression of imprinted transcript, as recently reported

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Eggermann et al. Clinical Epigenetics (2015) 7:123 Page 16 of 18

for the imprinted transcription factor PLAGL1, the gene Health (CP03/0064; SIVI 1395/09), Instituto de Salud Carlos III (PI13/00467)
responsible for TNDM [77]. Changes in imprinted gene and Basque Department of Health (GV2014/111017).

abundance occur due to increased transcription from the Author details

active allele in a DNA methylation independent fashion 1
Department of Human Genetics, RWTH Aachen, Pauwelsstr. 30, Aachen,
[78]. Recently, additional gene networks have been de- Germany. 2Molecular (Epi)Genetics Laboratory, BioAraba National Health
Institute, Hospital Universitario Araba, Vitoria-Gasteiz, Spain. 3Department of
scribed including the role of unoccupied insulin (IR) and Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical
insulin-like growth factor 1 receptor (IGF1R) signalling in Research Centre, Cambridge, UK. 4Human Genetics and Genomic Medicine,
the coordinated regulation of multiple imprinted genes as- Faculty of Medicine University of Southampton, Southampton, UK. 5Wessex
Clinical Genetics Service, Princess Anne Hospital, Coxford Road,
sociated with growth and development in mouse [79]. Southampton, UK. 6Clinical Genetic Clinic, Kennedy Center, Rigshospitalet,
Interestingly this regulation is independent of PLAGL1, Copenhagen University Hospital, Glostrup, Denmark. 7Imprinting and Cancer
despite this gene being downregulated by more than 80 % Group, Cancer Epigenetic and Biology Program (PEBC), Institut d’Investigació
Biomedica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Barcelona, Spain.
in the IR and IGF1R double knockout cells. 8
DiSTABiF, Seconda Università degli Studi di Napoli, Caserta, Italy. 9Institute of
Finally the paternally expressed non-coding RNA IPW Genetics and Biophysics—ABT, CNR, Napoli, Italy. 10Endocrinology and
located in the commonly deleted chromosome 15 region diabetology for children and reference center for rare disorders of calcium
and phosphorus metabolism, Bicêtre Paris Sud, APHP, Le Kremlin-Bicêtre,
in PWS regulates the levels of maternally expressed tran- France. 11INSERM U986, INSERM, Le Kremlin-Bicêtre, France. 12INSERM, UMR_S
scripts within the imprinted cluster on chromosome 14 938, CDR Saint-Antoine, Paris F-75012, France. 13Sorbonne Universites, UPMC
[80]. The transcriptional repression of the DLK1-DIO3 Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France. 143APHP,
Pediatric Endocrinology, Armand Trousseau Hospital, Paris, France.
locus by IPW is due to altered repressive histone modifi-
cations at the IG-DMR, which is independent of DNA Received: 14 July 2015 Accepted: 29 September 2015
methylation, via targeted recruitment of the histone meth-
yltransferase G9a. These observations support the reports
of affected individuals with TS14 who display PWS-like References
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