The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 175
In contrast to the size consistency and recurrent use of specific LCR sequences documented among
many of the interstitial SAS deletions, other deletions appear to have multiple independent
breakpoints and vary considerably in size. This size variability has been noted in association with
multiple deletions including those that involve the short arms of chromosomes 1, 4, and 5 (17,47,48).
Although the mechanism(s) responsible for these more variable deletions is currently unknown, recent
evidence suggests that LCRs might also be involved in the formation of at least some (5,6,49).
DUPLICATIONS
The term “duplication” as applied to chromosome abnormalities implies the presence of an extra
copy of a genomic segment resulting in a partial trisomy. A duplication can take many forms. It can be
present in an individual as a “pure duplication,” uncomplicated by other imbalances (see Fig. 6), or in
combination with a deletion or some other rearrangement. Examples of some types of rearrangement
that involve duplications include isochromosomes, dicentrics, derivatives, recombinants, and markers.
The origins and behavior of these abnormal chromosomes are discussed elsewhere in this chapter.
Tandem duplications represent a contiguous doubling of a chromosomal segment. The extra material
can be oriented in the same direction as the original (a direct duplication) or in opposition (an
inverted duplication). Most cytogenetically detectable tandem duplications in humans appear to be
direct (50).
Autosomal duplications produce partial trisomies and associated phenotypic abnormalities. As
mentioned in the Introduction, the phenotypes associated with duplications are typically less severe
than those associated with comparable deletions. Very few duplications, however, have occurred
with sufficient frequency or been associated with such a strikingly characteristic phenotype that they
have been recognized as defined clinical syndromes (see Table 2). A few cases of distal 3q duplication
have been reported in patients with features similar to Cornelia de Lange syndrome. However,
these patients also have additional abnormalities not usually associated with the syndrome (30).
Paternally derived duplications of distal 11p have also been associated, in some cases, with Beckwith–
Wiedemann syndrome (51). More intriguing, and perhaps more significant, is the emerging recognition
of recurring duplications that involve the same genomic segments that are associated with some
of the established microdeletion syndromes. These complementary microduplication/microdeletion
syndromes are thought to represent the reciprocal products of recurring unequal exchange events that
are mediated by flanking homologous LCR sequences. The causative unequal exchange events can
occur following misalignment of either sister chromatids or homologs, as shown in Fig. 1. At this
time, complementary microduplication/microdeletion syndromes have been documented for the
Prader–Willi/Angelman, Smith–Magenis, and DiGeorge syndrome critical regions.
Several proximal chromosome 17 short arm duplications involving the same loci that are deleted
in Smith–Magenis syndrome have now been reported. The same LCRs that mediate the common
Smith–Magenis syndrome deletion also appear to mediate the complementary duplication. Consistent
clinical features in these duplication patients include growth and developmental delay, as well as
dental and behavioral abnormalities (52).
Likewise, a handful of patients with a proximal chromosome 22 duplication that is complementary
to the DiGeorge syndrome deletion have now been reported in the literature (53–55). The
phenotypes reported in these patients are variable and range from nearly normal to severe. A number
of the features observed in these duplication patients, such as mental retardation and developmental
delay, palate abnormalities, conotruncal heart defects, absent thymus, and T-cell deficiency,
are also associated with DiGeorge syndrome. In fact, it is interesting to note that several of the
reported duplication patients were identified by a fluorescence in situ hybridization (FISH) (see
Chapter 17) study that was requested because of suspected DiGeorge syndrome. Unexpectedly, an
extra fluorescence signal representing the duplication, rather than a deletion, was seen within the
proximal long arm of chromosome 22.