The Principles of Clinical Cytogenetics - Extra Materials - Springer

Genomic Imprinting and Uniparental Disomy 519
the imprinting process (90). It appears that PWS is a contiguous gene syndrome; no PWS patient has
been reported who has a mutation of only one of the PWS region genes.
The clinical phenotype of AS patients is distinct from that of PWS (91). Briefly, it includes microcephaly,
ataxia, characteristic gait, inappropriate laughter, seizures, severe mental retardation, and
hypopigmentation. Approximately 70% of AS patients have a deletion of the same 4-Mb sequence at
15q11-q13 on the maternally derived chromosome 15 (72–74). From 2% to 5% are the result of
paternal UPD for chromosome 15 (76,77,79), 6–10% as a result of an abnormality of the imprinting
process, causing a paternal methylation imprint on the maternal chromosome 15 (80–82,84), and
4–6% as a result of a mutation within the AS gene (reviewed in ref. 92; see also refs. 70 and 85). In
contrast to PWS, mutation of a single gene, the gene for E6-associated protein (E6-AP) ubiquitinprotein
ligase (UBE3A) (maternal allele active) has been identified in some AS families and is considered
the candidate gene for AS (70,85). The imprinting of UBE3A is tissue-specific, being restricted
to the brain (93–95). More recently, another imprinted gene, ATP10C, mapped within 200 Kb telomeric
to UBE3A, has also been shown to be expressed only on the maternal allele (96). It is speculated that
ATP10C could be involved in phospholipid transport and could also contribute to the AS phenotype.
Both UBE3A and ATP10C are located at the distal part of the 15q11-q13 region.
In both PWS and AS patients with abnormalities of the imprinting process, Buiting et al. identified
inherited microdeletions in the 15q11-q13 region (97). They proposed that these deletions probably affect
a single genetic element that they called an “imprinting center” (IC). This AS/PWS-IC has been shown to
have a bipartite structure and overlaps the SNRPN promoter, with the AS-IC being only 35–40 Kb upstream
of the PWS-IC (98–100). Mutations or disruptions of the imprinting center impair the imprinting process.
These mutations can be transmitted silently through the germline of one parent, the one in whom the gene
is normally silent, but appear to block the resetting of the imprint in the germline of the opposite sex. Thus,
a female with a PWS-IC mutation will not have affected children. Her sons, however, if they inherit the
mutation and are therefore unable to reactivate the cluster of PWS genes in their germ cells, will be at risk
of having PWS children, both male and female. The opposite is true for AS; that is, a male with an AS-IC
mutation will not have affected children, but his daughters, if they inherit the mutation, will be at risk of
having AS children. These observations in PWS and AS indicate that the PWS genes are active only on the
paternal chromosome 15 and the AS gene is active only on the maternal chromosome 15. These two
syndromes serve as classical examples of genomic imprinting in humans.
Deletion, UPD, or IC disruption can all result in an abnormal methylation pattern of the PWS/AS
parental alleles. Therefore, the most cost-effective approach to laboratory diagnosis of PWS/AS is to
perform DNA methylation studies first. This will detect virtually all cases of PWS and approximately
80% of the cases of AS. If the result is abnormal, FISh to detect 15q11-q13 microdeletion, followed
by UPD studies, should be performed to determine the exact etiology. In the case of AS, UBE3A
mutation analysis can be considered when the methylation study is normal.
Beckwith–Wiedemann Syndrome
Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder associated with neonatal
hypoglycemia, abdominal wall defects, macroglossia, visceromegaly, gigantism, mid-face hypoplasia,
and a predisposition to embryonal tumors (seen in 7.5–10% of patients) including Wilms tumor
(most common), rhabdomyosarcoma, and hepatoblastoma (101,102) (see next section). Most cases
(85%) are sporadic. BWS is a multigenic disorder resulting from dysregulation of a number of
imprinted genes at the chromosome 11p15.5 region and is caused by several molecular mechanisms.
These include the following:
1. Paternal UPD for the p15 region of chromosome 11 in approximately 20% of sporadic cases (103,104).
2. Cytogenetic abnormalities involving 11p15, present in a small number (approximately 1%) of all BWS
patients. These include duplication of the paternal 11p15 region as a result of either a de novo rearrangement
or a familial translocation/inversion (105,106), and maternally inherited balanced rearrangements
involving 11p15 (106,107).