Segregation of Familial Abnormalities

Although most of the idiopathic abnormalities just described are sporadic, other clinical presentations can occur because of unbalanced segregation of familial chromosome abnormalities. In these cases, the underlying mechanism for the clinical phenotype is not the chromosomal abnormality itself, but rather its transmission in an unbalanced state from a parent who is a balanced carrier to the subsequent generation (see Table 6-1).

The mechanism of pathogenesis here is distinguished from the mechanism of nondisjunction described earlier in this chapter. In contrast to aneuploidy or uniparental disomy, it is not the process of segregation that is abnormal in these cases; rather, it is the random nature of events during segregation that leads to unbalanced karyotypes and thus to offspring with abnormal phenotypes.

In the case of balanced translocations, for example, because the chromosomes involved form a quadrivalent in meiosis, the particular combination of chromosomes transmitted to a given gamete can lead to genomic imbalance (see Fig. 5-12), even though the segregation is itself normal.

Another type of familial structural abnormality that illustrates this mechanism involves inversion chromosomes. In this case, segregation of the inverted chromosome and its normal homologue during meiosis is typically uneventful; however, unbalanced gametes can be produced as a result of the process of recombination occurring within the inverted segment, in particular for pericentric inversions (see Fig. 5-13). Different inversion chromosomes carry different risks for abnormal offspring, presumably reflecting both the likelihood that a recombination event will occur within the inverted segment and the likelihood that an unbalanced gamete can lead to viable offspring. This overall risk must be determined empirically for use in genetic counseling. Several well-described inversions illustrate this point.

A pericentric inversion of chromosome 3 is one of the few for which sufficient data have been obtained to allow an estimate of the transmission of the inversion chromosome to the offspring of carriers. The inv(3)(p25q21) originated in a couple from Newfoundland in the early 1800s and has since been reported in a number of families whose ancestors can be traced to the Atlantic provinces of Canada. Carriers of the inv(3) chromosome are normal, but some of their offspring have a characteristic abnormal phenotype associated with the presence of a recombinant chromosome 3, in which there is duplication of the segment distal to 3q21 and deficiency of the segment distal to 3p25. The other predicted unbalanced gamete, with a duplication of distal 3p and deficiency of distal 3q, does not lead to viable offspring. The empirical risk for an abnormal pregnancy outcome in inv(3) carriers is greater than 40% and indicates the importance of family chromosome studies to identify carriers and to offer genetic counseling and prenatal diagnosis.

Not all pericentric inversions have a risk for abnormal offspring, however. One of the most common inversions seen in human chromosomes is a small pericentric inversion of chromosome 9, which is present in up to 1% of all individuals. The inv(9)(p11q12) has no known deleterious effect on carriers and does not appear to be associated with a significant risk for miscarriage or unbalanced offspring; the empirical risk is not different from that of the population at large, and it is therefore generally considered a normal variant.