The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 195
sequences and/or other repetitive DNA sequences located within the short arms of the acrocentric
chromosomes has been proposed. Nonrandom suppression of one centromere appears to provide
mitotic stability to some of the dicentric Robertsonian chromosomes (73,127). In other cases, both
centromeres appear to be active. It is believed that because of their close proximity, both centromeres
are able to function as one in these dicentric chromosomes (128). It should be noted that current
nomenclature (see Chapter 3) still calls for the description of all Robertsonian translocations as
monocentric and that this is used in most laboratories.
Homologous Robertsonian Translocations
In contrast to nonhomologous Robertsonian translocations, de novo whole-arm exchanges involving
homologous or like chromosome pairs are very rare. They appear to be predominantly
monocentric (82,123) and several of them have been shown to form postmeiotically (87,129,130).
Although historically all such rearrangements were collectively called homologous Robertsonian translocations,
recent molecular studies have shown that approximately 90% of the chromosomes within this
category might actually be isochromosomes composed of identical rather than unique homologous arms
(82,83,86,131). Molecular studies exploring the parental origin of de novo homologous Robertsonian
translocations suggest that no parental bias exists. Equal numbers of maternally and paternally derived
isochromosomes have been reported, and true homologous Robertsonian translocations in balanced
carriers appear to be composed of both a maternal homolog and a paternal homolog.
Reproductive Risks for Carriers of Robertsonian Translocations
Carriers of Robertsonian translocations are at risk for miscarriages and for offspring with mental
retardation and birth defects associated with aneuploidy, and rarely, uniparental disomy (UPD) or the
inheritance of both copies of a chromosome pair from a single parent (see Chapter 19). The relative
risk for each of these outcomes is a function of the sex of the heterozygous parent and/or the particular
acrocentric chromosome involved. In theory, all chromosome segregations within the carrier parent
of a homologous Robertsonian translocation and all malsegregations within nonhomologous
Robertsonian carriers produce monosomic or trisomic conceptions. Because all potential monosomies
and most of the potential trisomies are lethal during the first trimester, miscarriage is not uncommon.
Only those Robertsonian translocation chromosomes containing chromosomes 21 or 13 are
associated with an increased risk for having liveborn trisomic offspring. Trisomy 22 occurring secondary
to a Robertsonian translocation could also represent a rare possibility. Because their risk for
aneuploidy is greater than that of the general population, it is recommended that all Robertsonian
translocation carriers be offered prenatal testing (see Chapter 12).
Occasionally, abnormal offspring with UPD have also been observed among the children of balanced
Robertsonian translocation carriers (27). UPD has been reported in association with both de
novo and familial, homologous, and nonhomologous translocations. Currently, the risk for UPD in a
fetus with a balanced nonhomologous Robertsonian translocation is estimated to be 0.6%, whereas
that for a fetus with a balanced homologous Robertsonian translocation is predicted to be approximately
66% (132). Among liveborn offspring with congenital anomalies who carry a balanced
nonhomologous or homologous Robertsonian translocation, the risk for UPD has been reported to be
4% and 100% (2/2 homologous Robertsonian cases studied), respectively (133). The higher incidence
of UPD noted in association with the balanced homologous Robertsonian translocations parallels
the observation that most of these translocations actually represent true isochromosomes. Because
both arms of a true isochromosome are derived from a single chromosome, by definition UPD should
be present in these balanced Robertsonian translocation carriers. Whether the risk for UPD varies
depending on whether the translocation is familial or de novo is not currently known.
Postzygotic correction of a trisomy through chromosome loss (trisomy rescue) is thought to represent
the most likely mechanism for UPD, although monosomy correction and gamete complementation
could occur as well (132–134). Current data indicate that UPD is most concerning when