The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 191
Fig. 17. The expected meiotic pairing configuration for the (1;9) translocation described in Figure 16. Each
of the 2:2 and 3:1 segregants typically produced during meiotic cell division are shown.
In addition to being inherited, reciprocal translocations can also occur as new or de novo mutations.
As discussed in the Introduction, the risk for an abnormal outcome associated with a de novo
apparently balanced rearrangement is always greater than that associated with an equivalent rearrangement
that has been inherited from a normal parent. The actual risk associated with a de novo
apparently “balanced” translocation has been reported to be approximately 6–9% (1). This is two to
three times the overall rate of congenital abnormalities observed in the population.
The (11;22) Translocation
The (11;22) translocation, with breakpoints within bands 11q23.3 and 22q11.2, is unique because it
represents the first recognized recurring constitutional reciprocal translocation in humans (see Fig. 18).
Evidence for a second recurring translocation, a 4;8 translocation with breakpoints at 4p16 and
8p23.1, has only recently been reported (see below).
More than 100 apparently unrelated families with this (11;22) translocation have been reported to
date. For many years, it was not known whether the ostensible recurrence of this translocation is best
explained by (1) the efficient transmission of a single ancient unique translocation through multiple
generations or (2) multiple independent translocation events between two susceptible regions. However,
we now know that the latter is true. Mapping studies involving many different unrelated families
have demonstrated that the translocation breakpoints cluster within long AT-rich palindromic
sequences. [A palindrome is a DNA sequence that contains two inverted regions that are complementary
to each other (104,105).] The breakpoints are located at the tip of the imperfect hairpin or cruciform
structures that are predicted to form. Palindromic sequences that are predicted to form hairpinlike
secondary structures have also been implicated in the formation of at least one other translocation, a
nonrecurring (17;22) translocation (12). Although exactly how these structures promote this translocation
is unknown, it has been suggested that they might be susceptible to nicking by hairpin-specific
nucleases. Once nicked, these structures would then become susceptible to other nucleases that produce
double-stranded breaks and further erosion of the palindromic DNA surrounding the initial nick