The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 169
given accurate genetic counseling regarding their reproductive risks and options. In situations where
a familial rearrangement is identified, it must be remembered that it is not just the immediate family
but distant relatives as well who could be at risk for having children with unbalanced karyotypes and
associated mental and/or physical abnormalities. By systematically karyotyping the appropriate individuals
in each generation, all those with elevated reproductive risks can be identified and appropriately
counseled regarding their risks and options. Although there has been some debate regarding the
appropriateness of karyotyping the phenotypically normal minors of balanced carriers, 50% of whom
would be expected to be balanced carriers themselves, there is a consensus that these children should
be referred for appropriate genetic counseling when they reach reproductive age.
The situation becomes a bit more complex when chromosome analysis of a bone marrow or tumor
specimen results in an apparently balanced rearrangement, not associated with any particular neoplasm,
in all cells examined. In these cases, it is imperative to ascertain whether such a rearrangement
represents a patient-specific acquired change (which can then be monitored during treatment, remission,
relapse, or any change in disease aggression) or a constitutional abnormality present from birth.
The reasons for this are twofold. First, from the point of view of the physician treating the patient, the
presence of any acquired cytogenetic change is significant (see Chapters 15 and 16). Alternatively,
demonstrating that the rearrangement is constitutional can be considered “good news,” because this
means that there are, in fact, no acquired chromosomal changes. Second, and equally important,
however, is to consider the potential reproductive consequences for the extended family. Because it
is necessary to focus on the treatment of the patient’s cancer, and because many of these patients are
elderly and well beyond childbearing age, reproductive issues associated with a familial chromosome
rearrangement are frequently overlooked. It should be clear from this chapter, however, that these
issues must be addressed. Genetic counseling is covered in detail in Chapter 20.
De Novo Rearrangements
Every chromosome rearrangement was at one time a new or de novo rearrangement that carried
the risks associated with an undefined entity. Children who carry unbalanced rearrangements, regardless
of whether they represent new mutations or an unbalanced form of a familial rearrangement,
almost inevitably demonstrate an abnormal phenotype. An imbalance is an imbalance regardless of
how it arose.
In contrast, accurate predictions regarding the phenotype of a child or fetus that carries an
apparently balanced de novo chromosome rearrangement are more difficult to make. In this situation,
we have no idea what has occurred at the molecular level within the rearrangement and we
have no family members with the rearrangement from whom inferences can be made. The risk
for an abnormal phenotype is therefore always higher for an individual with an apparently balanced
de novo rearrangement than for an individual who has inherited a similar rearrangement
from a normal parent. Obviously, these individuals also carry a significantly higher risk for
phenotypic abnormalities than their chromosomally normal counterparts. Several population
studies have shown, for example, that the incidence of de novo apparently balanced rearrangements
among the mentally retarded is approximately seven times that reported in newborns (24).
Apparently balanced de novo rearrangements detected at amniocentesis have also been associated
with a risk for congenital abnormalities that is twofold to threefold higher than that observed
within the general population (1).
A number of different mechanisms are thought to be responsible for the abnormal phenotypes
observed in children with apparently balanced de novo rearrangements. One possibility is that the
translocation is not truly balanced. As discussed above, structural rearrangements that appear balanced
at the microscopic level might actually contain large duplications and/or deletions at the
molecular level. Another possibility is that the rearrangement is “balanced” but a break has occurred
within a critical gene or its surrounding regulatory sequences such that the gene product or its