J Assist Reprod Genet (2009) 26:477–486

DOI 10.1007/s10815-009-9353-3

GENETICS

Genomic imprinting disorders in humans: a mini-review

Merlin G. Butler

Received: 25 August 2009 / Accepted: 6 October 2009 / Published online: 21 October 2009
# Springer Science + Business Media, LLC 2009

Abstract Mammals inherit two complete sets of chromo- Introduction

somes, one from the father and one from the mother, and
most autosomal genes are expressed from both maternal and This mini-review includes the clinical and genetic descrip-
paternal alleles. Imprinted genes show expression from only tion of five representative disorders useful from a diagnos-
one member of the gene pair (allele) and their expression are tic/clinical perspective. These include Prader-Willi and
determined by the parent during production of the gametes. Angelman syndromes (the first examples of genomic
Imprinted genes represent only a small subset of mammalian imprinting in humans), Silver-Russell syndrome,
genes that are present but not imprinted in other vertebrates. Beckwith-Weidemann syndrome, Albright hereditary osteo-
Genomic imprints are erased in both germlines and reset dystrophy and uniparental disomy 14 [1, 2]. Also, included
accordingly; thus, reversible depending on the parent of will be an introduction and description of genomic
origin and leads to differential expression in the course of imprinting in humans and assisted reproductive technology
development. Genomic imprinting has been studied in (ART). This review focuses on humans with limited
humans since the early 1980’s and accounts for several discussion pertaining to other mammals.
human disorders. The first report in humans occurred in Genomic imprinting is related to the methylation of
Prader-Willi syndrome due to a paternal deletion of cytosine bases in the CpG dinucleotides of the DNA
chromosome 15 or uniparental disomy 15 (both chromosome molecule which are key regulatory elements of genes.
15s from only one parent) and similar genetic disturbances Almost all imprinted genes have a CpG-rich differentially
were reported later in Angelman syndrome. methylated region (DMR) which usually relates to allele
repression. Many imprinted genes are arranged in clusters
Keywords Genomic imprinting . Human disorders . (imprinted domains) on different chromosomes under
Assisted reproductive technology . DNA methylation . control of an imprinting center affecting animal growth,
Prader-Willi syndrome . Angelman syndrome . Silver- development and viability. Imprinted genes may also
Russell syndrome . Beckwith-Wiedemann syndrome . contribute to behavior and language development, alcohol
Albright hereditary osteodystrophy . Uniparental disomy 14 dependency, schizophrenia, and possibly bipolar affective
disorders. In addition, the phenomena of genomic imprint-
ing with abnormal imprinting and loss of heterozygosity
contributes to a wide range of malignancies [3–5].
Capsule Disturbances in imprinted genes cause several human
diseases involving neurological disorders, obesity, diabetes and The expression of imprinted genes may be tissue- and
malignancies with expression patterns of imprinted genes potentially stage specific with one of the parental alleles being
influenced by the environment including assisted reproductive differentially expressed only at a certain developmental
technology. stage or in certain cells. However, the monoallelic
M. G. Butler (*) expression of an imprinted gene is not absolute. Thus, a
Departments of Psychiatry & Behavioral Sciences and Pediatrics, potential role of genomic imprinting in the differentiation of
Kansas University Medical Center,
tissue types may be to determine the transcription rate of
3901 Rainbow Boulevard, MS 4015,
Kansas City, KS 66160, USA genes that influence growth through a fine balance between
e-mail: mbutler4@kumc.edu the expression of the two parental alleles [6].
478 J Assist Reprod Genet (2009) 26:477–486

Experimental evidence suggests that genomic imprinting ment of higher order regulatory elements showing allelic
evolved about 150 million years ago in a common live-born specific DNA replication. Genes contributed by the mother
mammalian ancestor after divergence from egg-laying generally replicate or express at different rates than genes
animals [7]. Imprinting genes provide the paternal and contributed by the father. However, inappropriate methyl-
maternal genomes the ability to exert counteracting growth ation may contribute to tumor formation by silencing
effects during embryonic development [8]. Approximately tumor-suppressing genes or by activating growth-
1% of all mammalian genes are thought to be imprinted stimulating genes. In mammals, DNA methylation patterns
with the first gene (H19) reported to be imprinted in are established and maintained during development by
humans in 1992 [9]. Since then, many imprinted genes are three distinct DNA cytosine methyltransferases (Dnmt1,
now candidates for human disease including cancer, obesity Dnmt3a and Dnmt3b). In mammalian somatic cells,
and diabetes [7]. cytosine methylation occurs in 60–80% of all CpG
Imprinted genes are targets for environmental factors to dinucleotides that are not randomly distributed in the
influence expression through epigenetics whereby the genome. Heavily methylated heterochromatin and repetitive
expression level is altered without changing the DNA sequences contribute to gene silencing. Most CpG islands
nucleotide coding structure. Imprinting disturbances have located at the promoter regions of many active genes are
been reported in classical genetic disorders such as methylation free. Understanding the functions of DNA
Beckwith-Wiedemann, Angleman and Prader-Willi syn- methylation and its regulation in mammalian development
dromes while the incidence of these disorders are increased will help to elucidate how epigenetic mechanisms play a
in those individuals conceived with the use of assisted role in human diseases such as neurobehavioral problems
reproductive technology (ART). Hence, ART may increase and cancer [5, 15, 16].
imprinting defects by changing the regulation of imprinted Many imprinted genes are growth factors such as
genes [10]. insulin-like growth factors (e.g. IGF2 in Beckwith-
Epigenetics involve various processes altering gene Wiedemann syndrome) or as regulators of gene expression
activity without changing the primary nucleotide sequence controlling growth (e.g., the GRB10 gene in Silver-Russell
of the DNA molecule. A common process for controlling syndrome). Paternally expressed genes generally enhance
gene activity is methylation. A gene that is methylated growth, whereas maternally expressed genes appear to
(inactivated) can be reactivated in male or female gameto- suppress growth. Imprinting disorders are associated with
genesis for the next generation. For example, a maternally both genetic and epigenetic mutations or defects including
imprinted gene (inactivated by methylation) may be disruption of DNA methylation within the imprinting
unmethylated by male gametogenesis and transmitted as controlling regions of these genes. Some patients with
an active gene in the sperm. imprinting disorders such as Beckwith-Wiedemann syn-
A genome-wide search for imprinted genes in the human drome may have more generalized imprinting defects with
genome has identified over 150 candidate imprinted genes hypomethylation at several maternally methylated imprint-
involving 115 chromosome bands [11]. The number of ing controlling regions disrupting growth [17, 18].
human diseases or disorders, due to genomic imprinting In experimental studies, manipulation of mouse embryos
maybe greater than 100 conditions as a consequence of an has resulted in diploid embryos containing only diploid
inappropriate genetic alteration such as a deletion or paternal or maternal chromosomes. In embryos containing
uniparental disomy involving a gene or chromosome only a paternal genome, reduced fetal growth and a
region. Humans are predicted to have fewer imprinted proliferative extra-embryonic (placenta) growth occurs,
genes than mice, but the types of human genes involved are whereas embryos containing a diploid set of maternal
markedly different from mice [11]. Therefore, questions chromosomes maintain a relatively normal fetal growth
have been raised about the use of mice as models for pattern but exhibit poor extra-embryonic growth. The
human diseases, particularly those involved with imprinted process of turning on and off genes, particularly develop-
genes, and assessing environmental factors that may impact mental genes, is ongoing throughout the life cycle in
on genes and their activity. Examples of classical human mammals influenced by tissue specificity and timing
disorders related to alterations of genomic imprinting, [6, 19–22].
besides Prader-Willi and Angleman syndromes, include
Silver-Russell syndrome, Beckwith-Wiedemann syndrome,
Albright hereditary osteodystrophy and, more recently, Assisted Reproductive Technology (ART) and genomic
uniparental disomy 14 (both paternal and maternal forms) imprinting
[5, 12–14].
Genes clustered together under the regulation of a single Although imprinted genes account for only a small
imprinting-controlling element suggest possible involve- proportion of the mammalian genome, they play an
J Assist Reprod Genet (2009) 26:477–486 479

important role in embryogenesis particularly in the [33]. Because imprinting disorders are uncommon, larger
formation of visceral structures and the nervous system studies are needed to confirm an association between
[6]. Both mutations (causing DNA structure changes) and ARTs and imprinting disorders and which disorders are at
epigenetic modifications (affecting gene expression with- the highest risk.
out altering the nucleotide DNA structure) in somatic cells
disturb the expression of imprinted genes leading to
malformations and syndromes caused by genomic im- Examples of genomic imprinting disorders
printing defects. Therefore, manipulation of the cellular
environment could interfere with regulation of expression Prader-Willi syndrome
of imprinted genes and produce an abnormal outcome. For
example, in 1991, Willadsen [23] reported newborn calves Prader-Willi syndrome (PWS) is a complex genetic condi-
produced by embryo cloning showed malformations or tion characterized by mental and physical findings, with
disturbances in growth apparently due to the inability to obesity being the most significant health problem [34–36].
reprogram the somatic nucleus used in the cloning PWS is considered the most common genetically identified
procedure. Accelerated embryo growth, increased body cause of life-threatening obesity in humans and affects an
weight, and birth complications related to the large size estimated 350,000–400,000 people worldwide. Prader-Willi
were reported along with perinatal deaths [24]. Further- syndrome has been estimated to occur in one in 10,000 to
more, placental abnormalities and polyhydrammos were 20,000 individuals and present in all races and ethnic
sometimes observed in such pregnancies [25]. The large groups but reported disproportionately more often in
offspring size was probably due to disturbances of Caucasians [34].
expression of the insulin-like growth factor receptor PWS is characterized by infantile hypotonia, early
(Igf2r) gene [26] due to manipulations of the gametes or childhood obesity, short stature, small hands and feet,
from the early embryos through inadequate conditions of growth hormone deficiency, hypogenitalism/hypogonad-
the in vitro culturing techniques [27–29]. ism, mental deficiency and behavioral problems including
The use of ARTs with in vitro manipulation of temper tantrums and skin picking and a characteristic facial
gametes or from the early human embryos and potential appearance with a narrow bifrontal diameter, short upturned
factors impairing the expression of genes has received nose, triangular mouth, almond-shaped eyes, and oral
much attention in the medical community. According to findings (sticky saliva, enamel hypoplasia) [34, 36, 37].
Schieve et al. [30], infants conceived with the use of In 1956, Prader, Labhart, and Willi [38] were the first to
ARTs have low or very low birth weight compared to report this syndrome while Ledbetter and others [39] in
those conceived naturally. In a prospective study of 1981 were the first to report an interstitial deletion of the
Beckwith-Wiedemann syndrome (BWS), DeBaun et al. proximal long arm of chromosome 15 in the majority of
[28] reported the prevalence of ARTs as 4.6% (3 of 65 subjects. Butler and Palmer in 1983 [1] were the first to
subjects) versus the background rate of 0.8% in the United report that the origin of the chromosome 15 deletion was de
States. A total of seven children with BWS were born after novo or due to a new event and found that the chromosome
ART—five of whom were conceived after intracytoplas- 15 leading to the deletion was donated only from the father.
mic sperm injection. Molecular studies were performed on In about 70% of subjects with PWS, the 15q11-q13 deletion
six of the children and five had specific imprinting or was present while about 25% of individuals with PWS had
epigenetic alterations. Furthermore, in a current review of either maternal disomy 15 (both 15s from the mother) or
the literature on imprinting disorders and assisted repro- defects in the imprinting center controlling the activity of
ductive technology, Manipalviratn et al. [31] found that genes in the chromosome 15 region (about 5% of cases).
more than 90% of children with BWS born after ART had Rarely, other chromosome 15q11-q13 rearrangements occur
imprinting defects compared with 40–50% of children such as translocations. Occasionally, the father may have
with BWS conceived without ARTs. Independent studies inherited an imprinting defect on chromosome 15 from his
in the United States, United Kingdom and France showed mother and can pass on the defect to his offspring at a 50%
that the relative risk of BWS was significantly increased recurrence risk for PWS [36, 37].
by a factor of 3 to 6 fold if ARTs were used in establishing PWS is generally divided into two major stages of clinical
the pregnancy. Patients with Angelman syndrome with course development. The first stage is characterized by
complete or partial loss of methylation on chromosome 15 infantile hypotonia, temperature instability, a weak cry and
have also been reported to occur following the use of poor suck, and feeding difficulties with tube feedings often
ARTs [32]. In addition, infants with retinoblastoma, an required, developmental delay and underdevelopment of the
autosomal dominant eye tumor disorder with incomplete sex organs. The second stage occurs in early childhood (2–
penetrance, have been reported following the use of ARTs 4 years of age) and characterized by an insatiable appetite,
480 J Assist Reprod Genet (2009) 26:477–486

rapid weight gain and subsequent obesity without caloric and the distal breakpoint (BP3) in the 15q11-q13 region
restriction, continued developmental delay or psychomotor [42]. The typical PWS deletion consists of two classes, type
retardation. The average IQ is 65. Other features noted during I and type II, depending on the size and chromosome
the second stage include speech articulation problems, food breakpoint position (Fig. 1). Those with the larger typical
foraging, rumination, unmotivated sleepiness, physical inac- type I deletion (involving BP1 and BP3) have more clinical
tivity, decreased pain sensitivity, self-injurious behavior, problems such as obsessive compulsive disorders, self-
strabismus, hypopigmentation, scoliosis, obstructive sleep injury and poorer academic performance than those PWS
apnea, and abnormal oral pathology [34, 40]. In addition, subjects with the smaller type II deletions (involving BP2
those with the 15q11-q13 deletion are prone to hypopig- and BP3) [43]. These genetic subtypes are determined by
mentation and self-injurious behavior (skin picking). Those fluorescence in situ hybridization (FISH), genotyping and
with maternal disomy 15 have higher verbal IQ scores and methylation using DNA probes from the 15q11-q13 region.
better memory retention (Table 1) [35]. At least 70 nonredundant genes/transcripts are recog-
Obesity is the most significant health problem in PWS nized in the 15q11-q13 region, and at least a dozen genes
and may be life-threatening. Weight control and dietary are imprinted and paternally expressed. Methylation DNA
restrictions are key management issues with caloric intake testing which measures the methylation status of the genes
restricted to 6 to 8 calories per centimeter of height for in the region can be used for laboratory diagnosis of PWS.
weight loss beginning in early childhood and to 10 to 12 Methylation testing is considered to be 99% accurate in the
calories per centimeter of height to maintain weight. The diagnosis of PWS, but does not allow for identification of
use of human recombinant growth hormone therapy has the specific genetic subtype (deletion, maternal disomy or
resulted in a decrease in body weight and fat, an increase in an imprinting defect). Additional testing besides FISH is
muscle mass and physical activity and a higher quality of required to identify maternal disomy 15 or imprinting
life for PWS individuals [40]. defects such as genotyping of informative DNA markers
PWS and its sister syndrome, Angelman syndrome (AS) from the 15q11-q13 region. Several genes or transcripts
which has an entirely different clinical presentation, were mapped to the 15q11-q13 region that are imprinted, with
the first examples of genomic imprinting in humans. AS is most having only paternal expression, include SNURF-
characterized by seizures, severe mental retardation, ataxia SNRPN, small nucleolar RNAs (snoRNAs), NDN, MKRN3
and jerky arm movements, hypopigmentation, inappropriate and MAGEL2. Candidate genes for causing PWS are
laughter, lack of speech, microbrachycephaly, maxillary paternally expressed and maternally silenced, located
hypoplasia, a large mouth with protruding tongue, promi- within the chromosome 15q11-q13 region and involved
nent nose, wide spaced teeth, and usually a maternal 15q11- directly or indirectly in brain development and function.
q13 deletion. Although PWS is thought to be a contiguous For example, the promoter and first exon of SNURF-
gene syndrome with several imprinted (paternally SNRPN are integral components of the imprinting center
expressed) genes as candidates for causing the disorder, that controls the regulation of imprinting throughout the
AS is caused by a single imprinted (maternally expressed) chromosome 15q11-q13 region. A disruption of this
gene, i.e., UBE3A, a ubiquitin ligase gene involved in early complex locus will cause loss of function of paternally
brain development [41]. The 15q11-q13 region contains expressed genes in this region, leading to PWS [36, 37, 40,
about 6 million DNA base pairs and a large cluster of 44, 45].
imprinted genes causing the two syndromes along with a Two imprinted and maternally expressed genes (UBE3A,
non-imprinted domain. Novel DNA sequences have been ATP10C) have also been identified in this chromosome
identified with low copy repeats clustered at or near the two region. The UBE3A gene causes AS. Additional genes
major proximal chromosome breakpoints (BP1 and BP2) including the GABA receptors, GABRB3, GABRA5,

Table 1 Clinical and genetic findings in Prader-Willi syndrome

• First reported by Prader, Labhart and Willi [38] in 1956

• Hypotonia, poor suck, and feeding difficulties during infancy
• Characteristic face (small upturned nose, narrow bifrontal diameter, thin upper lip)
• Hyperphagia and early childhood obesity
• Hypogonadism/hypogenitalism
• Short stature, small hands and feet, growth hormone deficiency, hypopigmentation Mental deficiency (average IQ=65), behavioral problems
(skin picking, obsessive-compulsive disorder)
• Genetic subtypes (e.g., maternal disomy 15, type I or type II 15q deletions) show variation in clinical phenotype
• Paternal 15q11-q13 deletion (in about 70% of cases), maternal uniparental disomy 15 (in 25%) and imprinting mutations (in 5%)
J Assist Reprod Genet (2009) 26:477–486 481

Fig. 1 Ideogram of chromo-

somes 15, showing genes locat-
ed in the typical deletion region
of Prader-Willi syndrome. The
locations of genes in the region,
15q11-q13, and their imprinting
status are shown. The gene
disorder is based on the UCSC
Genome Bioinformatics website
(http://genome.ucsc.edu).
Approximately 40% of subjects
with the typical deletion have
the larger type I deletion, and
approximately 60% have the
smaller type II deletion.
Abbreviations: Cen, centromere;
Tel, telomere; BP, breakpoint;
IC, imprinting center; snoRNA,
small nucleolar RNA.
(Reproduced from Expert
Reviews in Molecular Medicine
(2005) Vol. 7, e14.)

GABRG3 and P (for pigmentation) have been identified in particularly of the limbs, and small incurved fifth fingers
this chromosome region and not imprinted but may play a (clinodactyly). Individuals with SRS have late closure of
role in the PWS phenotype. Recently, a small deletion the anterior fontanel, immature bone development and
involving the paternally expressed snoRNA (HBII-85) was excessive sweating of the head and upper trunk during
reported in an obese male with features of PWS, further infancy. Hypoglycemia may also be present in infancy and
supporting its role in the causation of PWS [46]. early childhood. Patients with this disorder frequently
Maternal disomy 15 is the second most frequent have café au lait spots and occasionally hypospadias,
finding in PWS thought due to fertilization of an oocyte cardiac defects or precocious puberty. Developmental
with two maternal chromosome 15s by a normal sperm delay can be seen. Although these patients are generally
with one chromosome 15. This leads to a zygote which is underweight and have feeding problems they gradually
trisomic for chromosome 15. This condition is not gain weight, but growth hormone deficiency is reported.
compatible with development and is a relatively common There is a large appearing head with large fontanels in
cause of early miscarriages. Through a trisomy rescue infancy resembling hydrocephalus (Table 2) [50].
event in the fetus, the pregnancy is salvaged and not Several abnormalities have been reported involving
spontaneously aborted. This leads to a normal set of chromosomes 7, 8, 15, 17, and 18, in the form of rings,
chromosomes, but with two maternal chromosome 15s in deletions, and translocations. However, the majority of
the fetus, producing PWS [47]. Silver-Russell syndrome patients have a normal karyotype.
Maternal disomy of chromosome 7, in which both
Silver-Russell syndrome chromosome 7s come from the mother, occurs in about
10% of subjects with SRS. Some SRS patients with
Silver-Russell syndrome (SRS) was first reported by maternal disomy 7 may have a milder phenotype [17, 50].
Silver et al. in 1953 [48] and by Russell in 1954 [49]. Although no single gene appears to be responsible for all
SRS affects approximately 1 in 75,000 births. SRS is the features seen in Silver-Russell syndrome, genetic
clinically heterogeneous with prenatal and postnatal evidence exists for involvement of two separate regions
growth retardation, a characteristic facial appearance on chromosome 7 including 7p11.2-p13 and 7q31-qter.
including a small, triangular face with frontal prominence Imprinted genes with only paternal expression involving
and a normal head circumference, growth asymmetry growth stimulation within the 7p13 band have been found
482 J Assist Reprod Genet (2009) 26:477–486

Table 2 Clinical and genetic findings in Silver-Russell syndrome

• First reported by Silver et al. [48] in 1953 and Russell [49] in 1954
• Small stature (prenatal onset)
• Skeletal asymmetry (in limbs)
• Characteristic face (small triangular, frontal prominence with normal head circumference, downturned corners of mouth, small chin)
• Small incurved fifth finger (clinodactyly)
• Abnormalities reported for chromosomes 7, 8, 15, 17 and 18 including rings, deletions, and translocations
• Maternal uniparental disomy 7 (in 10% of cases); 7p duplications or unknown (about 40%)
• Maternal duplication of chromosome 11p15 (5% of cases); hypomethylation of telomeric 11p15 imprinting center (40–60% of cases)

including MEST (mesoderm-specific transcript), PEG1 Beckwith-Wiedemann syndrome

(paternally expressed gene 1), carboxypeptidase A4
(CPA4), coatomer protein complex subunit gamma 2 Beckwith-Wiedemann syndrome (BWS) was first reported by
(COPG2) and two imprinted noncoding RNAs (MESTIT, Wiedemann in 1964 [54] and Beckwith in 1969 [55]. BWS is
C1T2/COPG2IT1) and become potential gene candidates generally sporadic but an autosomal dominant transmission
for this disorder. is reported in approximately 10–15% of cases. Major
The GRB10 (growth factor receptor-bound protein 10) features of this syndrome are macrosomia, with a large
gene is maternally expressed and located in the 7p11.2- muscle mass at birth and macroglossia, prominent eyes with
p13 region along with other genes involved in human periorbital fullness, and characteristic ear creases and /or pits.
growth and development such as IGFBP1, IGFBP3, Other features include capillary nevus flammeus over the
PHKG1, EGFR and GHRHR [17, 51]. The GRB10 gene central forehead and eyelids; a large fontanel; accelerated
acts as a suppressor of growth through its interaction with bone age; growth asymmetry; organomegaly involving the
either the (IGF1) receptor or the growth hormone receptor kidneys, liver, pancreas, and spleen; an omphalocele; and an
[52]. In addition, two patients with SRS have been increased intra-abdominal tumor rate, particularly of the
identified with cytogenetic duplications of 7p11.2-p13 kidneys and occasionally the liver. Additional findings may
encompassing the region containing the GRB10 gene. include neonatal hypoglycemia, present in about one-third of
Therefore, the explanation for maternal disomy 7 causing cases, cardiovascular defects, and cryptorchidism. The
features of SRS specifically growth anomalies, would mortality rate is estimated to be as high as 21%. The large
include two functional maternal copies (instead of one) of tongue may interfere with breathing and cause feeding
a growth inhibitor gene and/or the lack of paternally difficulties. The frequency of abdominal tumors (Wilms,
expressed growth promoter genes (e.g. MEST/PEG1). hepatoblastoma) in this disorder is estimated at 10–20%.
More recent studies have found genetic and epigenetic Tumor surveillance with abdominal sonograms and blood
mutations affecting the imprinting centers on chromosome and urine biomarkers are warranted (Table 3) [50, 56].
11p15 in about 60% of SRS patients [53]. Therefore, SRS The majority of patients with Beckwith-Wiedemann
represents the first human disorder with imprinting syndrome do not have a recognized chromosome abnor-
disturbances affecting two different chromosomes (i.e., mality but have errors in epigenetics, usually with
chromosome 7 and 11). Thus, a functional interaction of abnormal methylation of genes in the 11p15.5 region,
factors encoded by genes may exist between the two specifically H19 and IGF2. However, the 11p15.5 chro-
chromosomes. Human chromosome 11p15 contains a mosome band contains more than a dozen known
cluster of imprinted genes crucial for the control of fetal imprinted genes, both maternal and paternal. This large
growth. The expression of genes in this region is domain of contiguous imprinted genes includes IGF2
regulated by two imprinting control regions (ICR1 and (paternally expressed), H19 (maternally expressed),
ICR2). The telomeric ICR1 domain controls the expres- CDKN1C (maternally expressed), KVLQT1 (maternally
sion of H19, possibly functioning as a microRNA expressed), and KCNQ10T1 (LIT1) (paternally expressed).
precursor involved in post-transcriptional regulation of As noted earlier, genes in the 11p15 region are organized
specific mRNAs during vertebrate development, and into two separately controlled imprinted domains; a
IGF2, which is paternally expressed and involved with telomeric (ICR1) and centromeric (ICR2) domain. Other
stimulating fetal growth and development. Chromosome target sites or binding factors in the telomeric ICR1
11p15 epimutations reported in SRS are typically due to domain controls the transcription and regulation of IGF2
hypomethylation of the ICR1 domain; this results in and H19. Therefore, one of the most common epigenetic
suppression of IGF2 growth factor activity and reduced alterations in patients with Beckwith-Wiedemann syn-
growth in SRS patients [17, 53]. drome is the abnormal (biallelic) expression of IGF2 or
J Assist Reprod Genet (2009) 26:477–486 483

Table 3 Clinical and genetic findings in Beckwith-Wiedemann syndrome

• First reported by Wiedemann [54] in 1964 and Beckwith [55] in 1969

• Macrosomia with large muscle mass at birth
• Craniofacial features (macroglossia, prominent eyes, periorbital fullness, ear creases and/or pits)
• Omphalocele, hypoglycemia
• Organomegaly (kidneys, liver, spleen), abdominal tumors
• Hemihypertrophy
• Paternal uniparental disomy 11 (in 15% of cases); loss of imprinting of IGF2 (hypermethylation of telomeric imprinting center region) (in 5%);
mutations in CKN1C in centromeric imprinting center region (in 10%); hypomethylation of centromeric imprinting center region (about 50%);
unknown (15%)

insulin-like growth factor 2 gene encoding a fetal mitogen Albright hereditary osteodystrophy
which stimulates growth. This abnormal expression is due
to loss of imprinting. Thus, there appears to be a [Pseudohypoparathyroidism (PHP),
reciprocal coordinated relationship between the insulin- Pseudopseudohypoparathyroidism (PPHP)]
like growth factor 2 (IGF2) and H19 genes in cellular
growth and development. The maternally expressed H19 Albright [58] first reported this osteodystrophy condition in
gene encodes a polyadenylated-spliced message and is 1942 which is due to an end-organ resistance to the actions
assumed to act as a growth-suppressing agent [17, 18, 57]. of parathyroid hormone (PTH) and other hormones. Two
Mechanisms that increase expression of IGF2 include major variants have been described: PHP (PHP-Ia, PHP-Ib)
maternally derived translocations and inversions of chro- and PHPP. Individuals with PHP-Ia have features of Albright
mosome 11p15, duplications of the paternal chromosome hereditary osteodystrophy (AHO) and present with hypocal-
11p15, paternal disomy 11 (10–20% of cases of BWS) and cemia and hyperphosphatemia despite elevated serum para-
imprinting anomalies; all lead to BWS. Hypermethylation thyroid hormone levels. Resistance to thyroid stimulating
of the ICR1 domain accounts for about 5% of BWS cases. hormone and gonadotropins as well as growth hormone-
The centromerically located ICR2 domain regulates the releasing hormone and calcitonin can also occur in these
expression of CDKN1C, KCNQ1 and other genes on the affected individuals. Individuals with PPHP have the
maternal allele. The gene of another non-coding RNA in characteristic physical features of AHO, but show no
11p15, KCNQ1OT1 (LIT1), is localized in intron 9 of the evidence of resistance to parathyroid hormone or other
KCNQ1 gene and expressed on the paternal allele. It hormones. PHP-Ia and PPHP have been reported in the same
probably represses the CDKN1C gene. Loss of methyla- families, but are dependent on the parent of origin. Both
tion of the maternal ICR1 domain correlates with variants result from decreased activity of the alpha subunit of
expression of KCNQ1OT1 (LIT1). Mutations of the the membrane bound trimeric G subunit-regulatory protein
CDKN1C gene account for about 40% of familial BWS (GNAS). The function of this guanine nucleotide-binding
cases and 5–10% of sporadic cases. In BWS, ICR2 signaling protein is to couple membrane receptors for adenyl
hypomethylation and CDKN1C point mutations lead to cyclase activity thereby stimulating the secondary messen-
reduced expression of CDKN1C and overgrowth. Finally, ger, cyclic adenosine monophosphate (cAMP) [50, 59].
loss of imprint of KCNQ1OT1 (LIT1) accounts for about Genetic defects are associated with different forms of this
50% of BWS cases [18]. condition by involving the GNAS gene located at chromosome
Phenotype/genotype studies have shown an association 20q13.11. GNAS is a complex imprinted gene that produces
of hemihypertrophy and hypoglycemia in BWS, with multiple transcripts through the use of alternative promoters
altered methylation of both the KCNQ1OT1 (LIT1) and and alternative splicing. It encodes four main transcripts: G
H19 genes. Patients with Beckwith-Wiedemann syndrome protein subunit alpha (involved in AHO), XLAS (paternally
and tumors have been described with an altered H19 gene expressed), NESP55 (maternally expressed and encodes a
methylation. In addition, an association has been reported chromogranin-like neuroendocrine secretory protein) and the
with macrosomia and midline abdominal wall defects and A/B transcript (derived from the paternal GNAS allele).
altered methylation of the KCNQ1OT1 (LIT1) transcript. GNAS is involved in the pathophysiology of these disorders
Therefore, the imprinting interaction of contiguous genes through complex mechanisms and pathways [60].
clustered in the 11p15.5 region involved in this overgrowth The clinical features of AHO consist of small stature
syndrome and the genetically opposite effects seen in (final adult height 54 to 60 inches), moderate obesity,
Silver-Russell syndrome will require additional studies for mental deficiency (average IQ of 60), round face with a
clarification and understanding. short nose and short neck, delayed dental eruption and
484 J Assist Reprod Genet (2009) 26:477–486

Table 4 Clinical and genetic findings in Albright Hereditary Osteodystrophy (AHO) [Pseudohypoparathyroidism (PHP); Pseudopseudohypopar-
athyroidism (PPHP)]

• First reported in 1962 by Albright et al. [58]

• Small stature (final height, 54 to 60 inches) and short metacarpals
• Rounded face with short neck
• Delayed dental eruption or enamel hypoplasia
• Areas of mineralization in subcutaneous tissues with variable hypocalcemia and hyperphosphatemia
• Defects of the GNAS gene associated with different forms of PHP and PPHP depending on the parent of origin. For example, maternal
inheritance leads to PHP-Ia, i.e., AHO plus hormone resistance while paternal inheritance leads to PHPP or AHO without evidence of resistance
to parathyroid hormone

enamel hypoplasia, short metacarpals and metatarsals heterozygous inactivating GNAS mutations. Interestingly,
especially of fourth and fifth digits, short distal phalanx maternal inheritance of such a mutation can lead to PHP-
of the thumb, osteoporosis, areas of mineralization in Ia (AHO with hormone resistance) while paternal inher-
subcutaneous tissues including the basal ganglia, vari- itance of the same mutation leads to PHPP or AHO alone.
able hypocalcaemia and/or hyperphosphatemia and The nature of the imprinted mode of inheritance for
seizures. Occasional findings include hypothyroidism, hormone resistance could be explained by the predomi-
hypogonadism, lens opacity or cataracts, optic atrophy, nantly maternal expression of GNAS in certain tissues.
ocular degeneration and vertebral anomalies (Table 4) Patients with PHP-Ia lacking GNAS mutations, but display
[50, 61, 62]. the gene disturbance, are due to an imprinting defect and
Patients with PHP are subdivided into PHP-Ia and PHP- loss of imprint at the exon A/B differentially methylated
Ib, depending on the presence or absence of additional region (DMP) of the gene. In addition, a unique 3-Kb
hormone resistance and the AHO phenotype. Nearly all microdeletion that disrupts the neighboring STX 16 close
patients with PHP-Ia have mild hypothyroidism, hypogo- to the differentially methylated domain can cause PHP-I as
nadism and abnormal response to growth hormone releas- well and loss of imprint [59, 60].
ing hormone while those patients with PHP who present In summary, the pattern of inheritance of the GNAS gene
with PTH-resistance, but lack AHO features are defined as located at chromosome 20q13.11 that stimulates adenyl
having the PHP-Ib subtype. Most PHP-Ib cases are cyclase activity is responsible for both PHP-Ia and PPHP
sporadic, but some have occurred in families with an variants of the AHO syndrome with multiple transcriptional
autosomal dominant inheritance pattern with incomplete units. PHP-Ia and PPHP are caused by heterozygous
penetrance. Patients with PHP-Ib typically lack GNAS gene inactivating mutations in those exons of the GNAS gene
mutations; however, studies show that the inheritance encoding the alpha subunit of the stimulatory guanine
comes from a female exhibiting alteration in imprinting of nucleotide-binding protein and the autosomal dominant
the GNAS locus. The most consistent defect is loss of form of PHP-Ib is caused by heterozygous mutations
methylation in controlling elements regulating the imprint disrupting a long-range imprinting control element of
of the GNAS gene. In addition, a case of PHP-Ib was found GNAS. Both disorder variants have been reported in the
with paternal disomy of chromosome 20 [59]. same family and dependent on parent of origin, therefore
Those patients with PHP-Ia and features of AHO are due to imprinting. If the altered gene is inherited from the
reported with mutations of the GNAS gene as well as affected father with either PHP-Ia or PPHP, then PHPP
cytogenetic deletions of chromosome 20q including occurs in the offspring. If the inheritance of the same GNAS
GNAS. Patients with PHPP (or those AHO patients mutation is present in the mother with either PHP-Ia or
without evidence of hormone resistance) also carry PHPP, then the child will present with PHP-Ia.

Table 5 Clinical and genetic findings in uniparental disomy 14 (maternal and paternal)

• First reported in 1991 by Wang et al. [63] and Temple et al. [64]
• Clinical findings in maternal disomy 14 include growth retardation, congenital hypotonia, joint laxity, psychomotor retardation, truncal obesity
and minor dysmorphic facial features
• Clinical features are more severe in paternal disomy 14 including polyhydramnios, thoracic and abdominal wall defects, growth retardation and
severe developmental delay.
• Imprinting errors with imprinted locus at 14q32 including the paternally expressed DLK1 gene and maternally expressed GTL2 gene
• Uniparental disomy, copy number changes and disruption of regulatory sequences or mutations of a single active allele leads to the disorder
J Assist Reprod Genet (2009) 26:477–486 485

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