The Principles of Clinical Cytogenetics - Extra Materials - Springer

522 Jin-Chen Wang
UNIPARENTAL DISOMY
The term uniparental disomy (UPD) was introduced by Engel in 1980 (146). It describes a phenomenon
in which both homologs or segments of a chromosome pair are derived from a single parent. An
example of the latter is the paternal UPD for 11p15 in BWS described previously. Discussion here will
be restricted to uniparental disomies for entire chromosomes, of which there are two types. Uniparental
isodisomy describes a situation in which both copies of a chromosome are not only derived from one
parent but also represent the same homolog (i.e., two copies of the same exact chromosome). Uniparental
heterodisomy refers to both of one parent’s homologs being represented (i.e. both chromosomes of
the pair from the same parent). The type of UPD present is not always readily apparent, and it should be
noted that, because of the recombination that takes place during meiosis, UPD along the length of an
involved chromosome pair can be iso- for certain loci and hetero- for others.
Uniparental disomy for an entire chromosome can occur as a result of gamete complementation,
as suggested by Engel (146). Because aneuploidy is relatively frequent in gametes, the chance union
of two gametes, one hypohaploid, the other hyperhaploid for the same chromosome, will result in a
diploid zygote with UPD for that chromosome. Structural rearrangements, such as Robertsonian or
reciprocal translocations (see Chapter 9), increase the chance of meiotic malsegregation and thus
could predispose to UPD. This is best illustrated by the case reported by Wang et al. (147), in which
UPD for chromosome 14 was observed in a child with a paternal (13;14) Robertsonian translocation
and a maternal (1;14) reciprocal translocation (see Fig. 2 and Chapters 3 and 9). Studies in animals
also support this concept. Maternal or paternal disomies are readily produced in mice with intercrosses
between either Robertsonian or reciprocal translocation carriers (14).
Another mechanism for the occurrence of UPD is by “trisomy rescue” (148). The vast majority of
trisomic conceptuses are nonviable; they could survive to term only if one of the trisomic chromosomes is
postzygotically lost. In one-third of these cases, such loss will result in UPD in the now disomic cells (see
Fig. 3). Because the loss occurs postzygotically, mosaicism in such conceptuses is often observed, with
the trisomic cell line sometimes confined to the placenta (see Chapter 12). Another way of “rescuing” a
trisomic conceptus is by forming a smaller marker chromosome from one of the trisomic chromosomes
after losing most of its active genetic material. If the one chromosome that rearranged and became the
marker chromosome is the single chromosome contributed by one parent, the remaining two of the trisomic
chromosomes will be from the same parent and thus represent UPD for this chromosome pair.
A third possible mechanism for the occurrence of UPD is by duplication of the single chromosome
in monosomic conceptuses (149). In this case, uniparental isodisomy for the entire chromosome would
be observed.
Two mechanisms contribute to the phenotypic effects of UPD. Unmasking of a recessive gene can
occur as a result of uniparental isodisomy, in which the disomic chromosomes are homozygous. This was
illustrated initially in an individual with cystic fibrosis who had maternal uniparental isodisomy for chromosome
7 (149) and later in many other patients with recessive disorders and UPD (see below). The
second mechanism is the effect caused by imprinted genes on the involved chromosome. This is best
illustrated by PWS/AS patients who have no deletion of 15q11.2, but rather have UPD, as discussed
previously. In addition to these two mechanisms, in cases where UPD arises as a result of “trisomy rescue,”
the presence of a mosaic trisomic cell line in the placenta and/or fetus might modify the phenotype.
The number of reported UPD cases has recently been increasing rapidly. Of the 47 possible types
of UPD of whole chromosomes, 34 have been reported to date. Some provide clear evidence for
imprinting and some seem to suggest no such effect, whereas others will require accumulation of
additional data before their status in this regard can be determined.
upd(1)mat
At least five cases of maternal UPD for chromosome 1 have been reported. One patient had lethal
autosomal recessive Herlitz-type junctional epidermolysis bullosa as a result of homozygosity for a