The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 183
deficiencies. In general, then, large inversions are associated with a greater risk of producing abnormal
liveborn offspring, because the recombinant chromosomes associated with them carry small
duplications and deficiencies that have a greater probability of being compatible with survival. Furthermore,
the larger the inversion, the greater the likelihood that a recombination event within the
inversion loop will occur and form recombinant chromosomes. The opposite is true of small inversions
with large distal segments, which are usually associated with a very low risk of liveborn abnormal
offspring.
In addition to the size of the inverted segment, other factors must be considered when determining
the reproductive risk associated with any given pericentric inversion. Because monosomies are generally
more lethal than trisomies, an inversion that produces a recombinant with a very small monosomy
might be associated with a relatively high risk of abnormal offspring.
The nature of the genetic material in the inverted chromosomes can also be important. For instance,
both trisomy and partial monosomy of chromosomes 13, 18, and 21 are seen in liveborn infants with
birth defects and mental retardation. Once the duplications and deficiencies associated with the
recombinants from a particular inversion are identified, review of the medical literature for evidence
that these duplications and/or deficiencies are compatible with survival can aid in predicting the magnitude
of the risk associated with that particular inversion.
Another clue to the level of risk associated with a given inversion is the manner in which the
inversion was ascertained. If a balanced inversion is ascertained fortuitously (for instance during a
prenatal chromosome study because of advanced maternal age), the risk associated with such an
inversion is probably very low. On the other hand, an inversion that is ascertained through the birth of
an infant with anomalies secondary to the presence of a recombinant chromosome is associated with
a much higher risk, because the important question of whether the recombinant offspring is viable
has already been answered. Careful examination of the family history in both types of ascertainment
can provide additional important information in assessing risk.
Gardner and Sutherland reviewed several studies that contain data about the risks associated with
pericentric inversions and estimated the risk for an inversion heterozygote to have an abnormal child
secondary to a recombinant chromosome (29). This risk was estimated to be 5–10% in families ascertained
through an abnormal child and approximately 1% for families ascertained for any other reason.
For families segregating very small inversions, the risk of having a liveborn recombinant child
might be close to zero. In cases of recurring inversions, additional information about the risks can be
gained from studying the literature. In the case of the inversion (8)(p23q22) mentioned earlier, for
example, enough recombinant offspring have been observed to derive an empiric risk of 6% for a
heterozygote to have a liveborn recombinant child (61). Large inversions with distal segments that
have been seen in liveborn children as monosomies or trisomies might be associated with high risk
regardless of their mode of ascertainment in a particular family.
Paracentric Inversions
The presence of paracentric inversions in the human population was only appreciated after the
advent of chromosome banding, and they are still reported less frequently than pericentric inversions.
Their incidence has been estimated at 0.09–0.49 per 1000 (57). Recurring paracentric inversions
have been reported in the short arms of chromosomes 3 and 6 and in the long arms of chromosomes
7, 11, and 14. A recurring 11(q21q23) inversion has been observed in a large number of families in
the Netherlands (62) and in Canadian Hutterites (63). With the advent of FISH and other molecular
techniques, a number of submicroscopic recurring inversions have also begun to be identified in the
human genome.
Recent data suggest that heterozygosity for some recurring submicroscopic inversions confer susceptibility
to other nearby rearrangements involving the same chromosome. For example, a submicroscopic
inversion polymorphism that spans the same LCR sequences that mediate the recurring