The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 193
In contrast to the frequent reports of chromosomally unbalanced children who inherited the abnormal
chromosome 4, only one chromosomally unbalanced child who inherited the abnormal chromosome
8 has been reported. This child was reported to be less dysmorphic and have milder mental
retardation than her third cousin and other unrelated individuals reported in the literature who inherited
the derivative chromosome 4 (114).
It has recently been demonstrated that this particular (4;8) translocation is a recurring one, mediated
by nonallelic homologous recombination between olfactory receptor gene clusters located on
both chromosomes (7). Among the six individuals whose translocation breakpoints were examined,
the 8p23 breakpoint was confined to a single olfactory receptor cluster, whereas the 4p16 breakpoint
was distributed between two different clusters. Interestingly, the translocation was of maternal origin
in all five of the de novo cases examined and each transmitting mother was heterozygous for a submicroscopic
inversion at both 4p16 and 8p23. The 4p16 inversion seen in each of these mothers spanned
the two olfactory receptor clusters that serve as breakpoint sites for the (4;8) translocation. Similarly,
the 8p23 inversion spanned the distal olfactory receptor cluster involved in the (4;8) translocation
and a more proximally placed cluster. Presumably both of these submicroscopic inversions, like the
(4;8) translocation, were also mediated by these clusters. Of note, heterozygosity for the same 8p23
inversion polymorphism was also found in the transmitting parents of patients who carry several
other types of recurring chromosome 8 rearrangement that are mediated by the same 8p23 olfactory
receptor gene clusters implicated in the (4;8) translocation (64).
Heterozygosity for a submicroscopic inversion has also been reported in association with several
other chromosome rearrangements. In approximately 30% of the Williams syndrome families studied,
a submicroscopic inversion that spans the same LCR sequences that mediate the common 1.5-Mb
deletion was observed in the transmitting parent (45,46). This inversion was never seen within the
nontransmitting parent or within any of the 26 unrelated control individuals who were examined.
Similarly, as discussed previously, Jobling et al. have reported an association between the presence
of a submicroscopic Y chromosome short arm inversion and short arm translocations between the X
and Y chromosomes, leading to the formation of XX males and XY females (65). How heterozygosity
for small inversions promotes the formation of these chromosome rearrangements is not currently
known. It has been suggested, however, that these rearrangements might be the consequence of abnormal
homologous chromosome pairing caused by the presence of heterozygosity for the associated
inversion (see the section Paracentric Inversions above).
ROBERTSONIAN TRANSLOCATIONS
A Robertsonian translocation occurs when the long arms of any two acrocentric chromosomes
(13,14,15,21,22) join to produce a single metacentric or submetacentric chromosome (see Figs. 19
and 20). Although these translocations might in fact be reciprocal, the small complementary chromosome
composed of short arm material is only occasionally seen, presumably because it is typically
acentric and, therefore, lacks the stability conferred by a centromere (115). Balanced carriers of
Robertsonian translocations therefore typically have 45 chromosomes rather than the usual 46. The
only notable genetic material within the short arm region of each of these chromosomes is a nucleolar
organizer region composed of multiple copies of the ribosomal RNA genes. Because this is redundant
information, loss of this material from the two chromosomes involved in the translocation is therefore
not clinically significant. It has been suggested that the close association of these nucleolar organizer
regions within the cell nucleus could promote the formation of Robertsonian translocations.
Since Robertsonian translocations were first described by WRB Robertson in 1916, we have
come to recognize that these translocations are among the most common balanced structural
rearrangements in the human population (116). Numerous studies examining both spontaneous
abortions and liveborn individuals indicate a frequency of approximately 1/1000 (117–119).
Although pairwise association of the 5 human acrocentric chromosomes can form 15 different