The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 171
homologous regions that now differ with regard to their chromosomal location and/or orientation
(see the sections Translocations, Inversions, Insertions, and Duplications). Chromosome malsegregation
and/or particular recombination events within these complex configurations can then lead to
unbalanced conceptions, many of which never implant or are spontaneously lost during gestation.
Cytogeneticists are frequently asked to make predictions regarding a balanced carrier’s risk of
producing an abnormal liveborn child. Although this is a legitimate question it is in practice very
difficult to answer accurately. One source of difficulty is the fact that, with very few exceptions, each
family’s rearrangement is unique. Therefore, unless a family is large and accurate information regarding
the reproductive history and phenotype of each family member is available, typically no empiric
data are available from which to obtain risk values. A second source of difficulty one encounters in
assessing the reproductive risks associated with a particular balanced rearrangement is the breadth
and complexity of the variables involved.
One important factor that is considered when assessing the reproductive risks of a carrier parent is
the extent of imbalance demonstrated by the potential segregants. In general, the smaller the imbalance,
the less severe the phenotype and the more likely the survival. An additional rule of thumb is
that the presence of extra genetic material is less deleterious than the absence of genetic material.
Another variable to be considered is the quality of the genetic information involved. Some chromosomes,
such as 16 and 19, are infrequently involved in unbalanced structural rearrangements. Presumably,
this occurs because of the importance of maintaining a critical dosage for a gene or group of
genes on these chromosomes. Conversely, imbalances involving other chromosomes such as 13, 18,
21, X, and Y appear to be more easily tolerated. In fact, a complete trisomy involving any of these
chromosomes is survivable.
Each family’s reproductive history can also provide important clues regarding the most likely
outcome for an unbalanced pregnancy. As one might expect, those families or individuals who have
had a liveborn child or children with congenital abnormalities, especially those where an unbalanced
form of the familial rearrangement has been documented, are at highest risk for having unbalanced
offspring. In families or individuals in whom multiple spontaneous abortions and/or infertility are
noted, the risk for liveborn unbalanced offspring would be expected to be lower. In these families, it
is assumed that the unbalanced conceptions are being lost very early as unrecognized pregnancies
(infertility) or later during gestation. Interestingly, the sex of the carrier parent also, in some cases,
influences the risk of having unbalanced offspring. In situations where a sex bias does exist, the
female carrier invariably possesses the higher risk. Why male carriers appear to produce fewer unbalanced
offspring than their female counterparts is not known. Perhaps fewer unbalanced segregants
form during spermatogenesis relative to oögenesis, and/or the selective pressure against unbalanced
gametes is greater in the male, and/or imprinting effects might cause the unbalanced embryos of male
carriers to be less viable than those of their female counterparts. Male infertility could also play role
(15,26) (see Chapter 11).
On rare occasions, an abnormal phenotype is observed in an apparently balanced carrier of a
familial rearrangement. Although some of these cases could simply represent coincidental events,
other possible explanations exist as well. Very rarely, abnormal offspring resulting from uniparental
disomy, or the inheritance of both homologous chromosomes from a single parent, has been documented
in the offspring of balanced translocation carriers (27) (see Chapter 19). Incomplete transmission
of a partially cryptic rearrangement has also been observed in the abnormal offspring of a
phenotypically normal carrier parent. Wagstaff and Herman, for example, describe a family in which
an apparently balanced (3;9) translocation was thought to be segregating (28). After the birth of two
phenotypically abnormal offspring with apparently balanced karyotypes, molecular analysis demonstrated
that the father’s apparently balanced (3;9) translocation was actually a more complex rearrangement
involving a cryptic insertion of chromosome 9 material into chromosome 8. Abnormal
segregation of this complex rearrangement led to a cryptic deletion of chromosome 9 material in one
sibling and a duplication of the same material in the other.