Review Article

The Impact of Nondisjunction in Humans: Not only numerical Chromosome Aberrations, but more.

Albert Schinzel

Institut für Medizinische Genetik der Universität Zürich, Schweiz

The importance of chromosome nondisjunction for the formation of numerical chromosome aberrations, especially trisomy, is well known. Numerical chromosome aberrations constitute the vast majority of chromosomal imbalance in human, both in live-borns and in spontaneous abortions (whereby 45,X and triploidy have higher incidences than any single trisomy). Recent molecular studies have confirmed the overwhelming contribution of maternal meiotic non-disjunction to autosomal trisomy and sex chromosomal hyperdiploidy. Exceptions include 47,XYY (always paternal), 47, XXY (about one half due to paternal non-disjunction) and 48,XXYY (always three sex chromosomes [X,Y,Y] from the father and only one X from the mother). However, it has been shown that the impact of non-disjunction goes beyond the aneuploidy of whole chromosomes.

Additional marker chromosomes. Patients have been described with additional isochromosomes for the short arm of chromosome 8, 9, 12 and 18. Tetrasomy and mosaic-tetrasomy for the short arm of these chromosomes cause highly specific malformation syndromes, e.g. the Pallister-Killian syndrome (mosaic-tetrasomy 12p) or tetrasomy 9p. Advanced mean maternal age has for long time been noted in series of families with an offspring having one of these additional isochromosomes. Molecular studies in families with a proband with additional isochromosome 18p have shown that the overwhelming majority have three alleles for some 18p markers which implies meiotic origin. With one exception (Eggermann et al. 1997), in all cases so far reported the extra chromosome was maternal in origin. In most informative families maternal heterozygosity for markers close to the centromere was reduced to homozygosity while maternal heterozygosity for markers mapping to distal 18p retained heterozygosity. Thus, it seems that the most likely origin of these cases is through maternal meiosis II non-disjunction as a first step, leading to a trisomic zygote, followed by centromeric misdivision or isochromosome formation and loss of the long arm of the additional chromosome. The predominance of meiosis II over meiosis I non-disjunction in these cases is parallel to the situation in "free" trisomy 18 where, in contrast to trisomy 13 and trisomy 21, meiosis II non-disjunction is more frequent than meiosis I non-disjunction. Examination of patients with tetrasomy 12p mosaicism (through isochromosome formation) revealed similar findings, i.e. predominantly maternal origin and reduction of maternal heterozygosity to homozygosity for markers on proximal 12p and non-reduction of markers on distal 12p. Again, a maternal (second) meiotic nondisjunction and subsequent isochromosome formation seems to be the most likely origin. Moreover, the same presumed origin was also found for additional isochromosomes 9p and one case mosaic for additional isochromosome 8p (Fisher et al. 1993; Dutly et al. 1998).

Additional isodicentric chromosomes are known for chromosomes 15 (with breakpoint mostly at q13 or distal q12) and for chromosome 22 (with breakpoint at q11 slightly proximal of the DiGeorge syndrome critical region). The phenotype of the former (partial tetrasomy 15) is characterized by severe mental retardation and epilepsy with normal growth and no or only very mild dysmorphic features (Schinzel 1984) while the latter (partial tetrasomy 22) has a very distinct clinical phenotype (the cat-eye syndrome) characterized by normal or mildly to moderately delayed mental development in combination with an array of very variable congenital malformations, including coloboma of iris/retina, anal atresia with fistula, congenital heart defect, especially totally anomalous pulmonary venous return, renal anomalies, down-slanting palpebral fissures and preauricular fistulas and/or tags, and rarer microtia (Schinzel et al. 1981). For cases with additional isodicentric chromosome 15 (q12/q13), advanced mean maternal age is a known feature (Schinzel 1984). Molecular investigation suggested meiotic nondisjunction as a first step leading to trisomy 15 and followed by formation of an isodicentric chromosome as a second rearrangement. In all of these instances except for tetrasomy 18p, the secondary rearrangement leading to an isochromosome or isodicentric chromosome is the basis of intrauterine survival since non-mosaic trisomy of these chromosomes (8, 9, 12, 15, 22) is in general lethal.

Another example of how meiotic nondisjunction may constitute one (the first) step towards chromosomal pathology is uniparental disomy (UPD). Not all instances of UPD result in an abnormal phenotype. Robinson et al. (1991) were the first to show that maternal UPD 15 is responsible for a substantial proportion of Prader-Willi syndrome patients and that it's incidence correlates with increased mean maternal age in a similar fashion as trisomy 21. This finding is in agreement with the observation that maternal UPD is mostly heterodisomy while paternal UPD is mostly isodisomy. Therefore, despite of reduction to homozygosity in maternal UPD, most instances of autosomal recessive gene defects in UPD patients will have paternal UPD. In a recent study, Ginsburg et al. (1998) compared the incidence of deletion versus UPD Prader-Willi (PWS) and Angelman (AS) patients and of non-UPD versus UPD Silver-Russell syndrome cases between those patients born to mothers below and those above 35 years of age at delivery. In all 3 instances, the proportion of UPD cases was at least 5 times higher in the group born to the "older" mothers. In addition, we also investigated a group of patients with etiologically unclassified congenital developmental defects born to mothers aged 35 year or older at delivery. We found 3 instances of UPD including one with maternal UPD 14, one with paternal UPD 15 and the Angelman syndrome phenotype which was not recognized at the first examination, and one with maternal UPD 16 except for segments 16p13 which, in a proportion of cells, was translocated to 1p (Schinzel et al. 1997). The aberration had escaped 2 previous chromosome examinations, one pre-, the other postnatally. Therefore, this child started as a zygote with maternal trisomy 16, and subsequent translocation of the paternal 16p13 segment to 1p and loss of the "free" paternal 16 led to the complex aneuploidy. Preliminary results in some other cases of similar aberrations disclosed further instances of mosaic-UPD evidencing that a substantial number of structural aberrations, especially in mosaic state, presumably start from meiotic nondisjunction and are formed by subsequent postzygotic structural rearrangements.

Among the cases in Ginsburg et al.'s (1998) study is one of paternal isodisomy 15 born to a 38 year-old mother. On the first glance this seems to be a chance event as the reduplication (1) affected the paternal homologue and (2), as always in isodisomy, presumably occurred after the zygote formation. However, advanced maternal age was also shown for other cases of paternal UPD 15 (Bottani et al. 1994) and hence is unlikely to be a random finding. The most plausible explanation for advanced age in connection with paternal isodisomy is that old mothers probably have an excess of both hyperhaploid and (complementary) hypohaploid gametes. The hyperhaploid gametes, however, can rarely be demonstrated as they will generally lead to early demise of the fetus monosomic for one chromosome. Only if reduplication of the complementary paternal chromosome occurs very early after zygote formation, will the fetus survive with paternal UPD, and only these cases can be demonstrated by molecular examinations. If this is the case, and if hypohaploid female gametes are as frequent as hyperhaploid ones, the number of zygotes monosomic for one chromosome is probably considerable, and fetal monosomy would lead to an even higher abortion rate than is known to be caused by fetal trisomy although these abortions occur far earlier than the latter and thus cannot be examined.

Summary

Nondisjunction leading to autosomal trisomy or sex chromosome aneuploidy constitutes the major cause of chromosomal aberrations, both in live-borns and - even more, in spontaneous abortions. Recent studies, however, have shown that meiotic nondisjunction is also the first step leading to some structural chromosome aberrations, particularly to almost all cases of additional isochromosomes or isodicentric chromosomes. Moreover, some mosaic duplications also start from meiotic trisomy, followed by reduction to uniparental disomy and formation of structural aberrations. Most instances of maternal UPD start from meiotic trisomy with concordant or subsequent loss of the paternal homologue. In addition, advanced mean maternal age in cases of paternal UPD suggests that meiotic nondisjunction may also result in hypohaploidy which would then constitute a major cause of very early fetal demise and occasionally may result in paternal UPD.

Address of the Author:

Albert Schinzel
Institut für Medizinische Genetik
der Universität Zürich
Rämistr. 74
CH-8001 Zürich, Switzerland
Tel. +41-1-634.25.21
Fax +41-1-634.49.16
schinzel@medgen.unizh.ch

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