The Principles of Clinical Cytogenetics - Extra Materials - Springer

134 Jin-Chen Wang
“gene-rich” chromosomes are less likely to survive. Trisomies 13, 18, and 21, which involve chromosomes
that are less “gene rich,” are therefore relatively “mild” and fetuses can survive to term.
This chapter addresses only those autosomal aneuploidies, both trisomies and monosomies, that have
been observed in liveborns. Polyploidy, or changes in the number of complete sets of chromosomes, are
also included, as are aneuploidies that are the result of supernumerary “marker” chromosomes.
MECHANISM AND ETIOLOGY
Errors in meiosis (nondisjunction) result in gametes that contain abnormal numbers of chromosomes
and, following fertilization, produce aneuploid conceptuses. Using DNA markers, the parental
origin of the additional chromosome in autosomal aneuploidies has been studied for trisomies 2, 7,
13, 14, 15, 16, 18, 21, and 22 (2,13–26). These studies suggest that most trisomies are of maternal
origin, but that the proportion varies among different chromosomes and that, with the exception of
chromosomes 7 and 18, nondisjunction in maternal meiosis stage I accounts for the majority of cases
(see Table 1).
The association between autosomal aneuploidy and maternal age has long been recognized. In
1933, Penrose demonstrated that maternal age was the key factor for the birth of Down syndrome
children (27). Why aneuploidy is maternal-age-dependent and what constitutes the mechanism and
etiology of chromosomal nondisjunction have been topics of much research, as summarized below.
Nondisjunction can occur during either meiosis I (MI) or meiosis II (MII). In MI, homologous
chromosomes pair and form bivalents (see Chapter 2). Malsegregation of homologous chromosomes
can occur in one of two ways. The first involves nondisjunction of the bivalent chromosomes with
both homologs going to the same pole (see Fig. 1d,e). This mechanism, as shown by Angell, can be
a very rare occurrence (28). The second type of error involves premature separation of the sister
chromatids of one homolog of a chromosome pair. Subsequent improper distribution of one of the
separated chromatids results in its segregation with the other homolog of the chromosome pair (29)
(see Fig. 2d,e). In MII, sister chromatids separate. Malsegregation occurs when both chromatids go
to the same pole (see Fig. 3g,h). Cytogenetic studies of oöcytes, performed mostly on unfertilized or
uncleaved specimens obtained from IVF programs, have provided conflicting results regarding
whether the frequency of aneuploidy actually increases with maternal age (30–33). However, a FISH
study of human oöcytes using corresponding polar bodies as internal controls demonstrated that nondisjunction
of bivalent chromosomes (MI error) does increase with maternal age (34), and a recent
study using multiplex FISH on fresh, noninseminated oöcytes also indicated an increase in premature
separation of the sister chromatids in MI with increasing maternal age (35). More data are needed
before a firm conclusion can be drawn. If confirmed, these latter studies will provide direct evidence
that a maternal-age-dependent increase in the frequency of MI errors is the basis for the observation
that the risk of having a trisomic offspring is greater in older women. In contrast, the “relaxed selection”
hypothesis assumes that older women are less likely to spontaneously abort trisomic conceptions
(36,37). However, data obtained from fetal death (38) and from comparison of frequencies of trisomy
21 between the time of chorionic villus sampling and the time of amniocentesis (39) suggest that
selective miscarriage is actually enhanced with increasing maternal age.
If maternal MI nondisjunction does increase in older women, what then causes this? Different
mechanisms have been proposed. One example is the “production line” hypothesis (40). This theory
proposes that oöcytes mature in adult life in the same order as the corresponding oögonia entered
meiosis in fetal life. Oögonia that enter meiosis later in development might be more defective in the
formation of chiasmata and, thus, more likely to undergo nondisjunction. The first direct cytological
support for this hypothesis was provided by a study that examined the frequency of unpaired homologs
in MI pachytene and diplotene in oöcytes obtained from abortuses at 13–24 weeks and 32–41
weeks of gestation (41). Of the six chromosomes studied (chromosomes X, 7, 13, 16, 18, and 21), the
rate of pairing failures in early specimens (0–1.2%) was significantly lower than that in later specimens