The Principles of Clinical Cytogenetics - Extra Materials - Springer

168 Kathleen Kaiser-Rogers and Kathleen Rao
female gametogenesis are thought to affect our respective predispositions to producing specific types
of de novo rearrangements, other factors, such as the effect of imprinting on fetal survival, have also
been proposed to play a role (see Chapter 19).
In theory, chromosome breakage, rearrangement, and reunion can occur during meiosis or mitosis.
Meiotic errors, because they occur prior to conception, would be expected to be present in every
cell of the resulting pregnancy. Postconception mitotic errors, in contrast, would be predicted to
produce a mosaic pregnancy containing both normal and abnormal cells. Interestingly, with the exception
of mitotically unstable chromosomes such as rings or dicentrics, structural chromosome rearrangements
are rarely seen in mosaic form. Although this observation suggests that many structural
rearrangements might be formed during meiosis, ascertainment bias likely plays a role as well.
Because mosaic individuals typically have milder phenotypes than comparable nonmosaics, they are
less likely to be ascertained and karyotyped. This would be especially true of individuals carrying
mosaic balanced rearrangements. Additionally, mosaicism is difficult to detect, particularly when it
is limited to a specific tissue or group of tissues, is present at a low level, and/or involves a subtle
structural change.
Differentiating Between Balanced and Unbalanced Structural Rearrangements
Structural rearrangements are often divided into two general categories: balanced and unbalanced.
Balanced rearrangements contain no net loss or gain of genetic information and the individuals who
carry them are generally phenotypically normal. In contrast, additional and/or missing genetic material
is present in individuals who carry unbalanced rearrangements. Just as modifications in the
amount of the various ingredients added to any recipe cause changes in the final product, deviation
from the normal disomic genetic complement results in a clinically affected individual.
Although it is easy to define balanced and unbalanced rearrangements, distinguishing between a
truly balanced and an unbalanced rearrangement using traditional cytogenetic techniques is often
impossible. The maximum level of resolution obtained using standard microscopy of G-banded
prometaphase chromosomes is reported to be 2–5 Mb or 2–5 × 106 bp. This number will vary, however,
depending on the quality of the chromosome preparations and the skill of the cytogeneticist
examining the karyotype(s). The ability to resolve or identify a rearrangement will also be influenced
by the degree to which the banding pattern, overall size, and centromere location of an involved
chromosome is altered. Obviously, the more apparent the change, the more likely it is to be detected.
A number of molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH),
24-color karyotyping, and comparative genomic hybridization (CGH) are currently being used to
detect submicroscopic or otherwise cryptic rearrangements that cannot be detected using traditional
cytogenetics (see Chapter 17).
Associated Risks
Once a structural chromosome rearrangement is detected, regardless of whether it is balanced or
unbalanced, the subsequent steps to take depend on the type of specimen that was analyzed.
For prenatal samples or children, parental karyotypes should be obtained to assess whether the
rearrangement has been inherited or represents a de novo mutation. If neither parent is found to be a
carrier of the rearrangement, the most likely scenario is that it represents a de novo abnormality rather
than an inherited one. Because the possibility of gonadal mosaicism can never be excluded, this
family would be given a very low risk of having another child with the same structural abnormality.
Prenatal testing would also be offered for all future pregnancies.
In contrast to the very low recurrence risk quoted to a couple with a child or pregnancy carrying a
de novo rearrangement, the risk of chromosomally abnormal conceptions for an adult who carries a
balanced structural rearrangement is much higher. In fact, for some familial rearrangements, the risk
can approach 50%. Therefore, it is imperative that these families be identified so that they can be