Analysis of two 47,XXX males reveals X-Y interchange and maternal or paternal nondisjunction

Summary Two cases of 47,XXX males were studied, one of which has been published previously (Bigozzi et al. 1980). Analysis of X-linked restriction fragment length polymorphisms revealed that in this case, one X chromosome was of paternal and two were of maternal origin, whereas in the other case, two X chromosomes were of paternal and one of maternal origin. Southern blot analysis with Y-specific DNA probes demonstrated the presence of Y short arm sequences in both XXX males. In one case, the results obtained pointed to a paracentric inversion on Yp of the patient's father. In situ hybridization indicated that the Y-specific DNA sequences were localized on Xp22.3 in one of the three X chromosomes in both cases. The presence of Y DNA had no effect on random X inactivation. It is concluded that both XXX males originate from aberrant X-Y interchange during paternal meiosis, with coincident nondisjunction of the X chromosome during maternal meiosis in case 1, and during paternal meiosis II in case 2.     

The origin of an extra chromosome 21 in families of children with Down syndrome

These are the first studies on the origin of nondisjunction of trisomy 21 in the USSR. Parental contribution was established in 84 of 140 families observed. In 66% cases the nondisjunction took place in oogenesis and in 34% cases - in spermatogenesis. Among the children, who inherited the additional chromosome from father, boys predominate. Compilative work on all the data available concerning the origin of the 21 nondisjunction has been performed; the factors favouring nondisjunction in I and II mitotic divisions in female meiosis, both genetical and age-dependent, have been considered. The great importance of the disturbances taking place in spermatogenesis for etiology is emphasized. It is proved that somatic hyperploidy does not serve as an indicator of predisposition for chromosome nondisjunction in meiosis.     

A 48,XXY,+21 Down syndrome patient with additional paternal X and maternal 21

Summary The origin of meiotic nondisjunction of the extra chromosomes X and 21 was studied in a patient with the karyotype 48,XXY,+21 using DNA polymorphisms. The extra chromosome X was the result of paternal first meiotic nondisjunction of X and Y. The extra chromosome 21 was derived from the mother. The meiotic error in the mother most probably occurred in meiosis II. Thus, this is a combination caused by the chance occurrence of two independent events.     

Nondisjunction in trisomy 21: origin and mechanisms

Chromosomal aneuploidy is a fundamental characteristic of the human species. In this review we summarize the knowledge about the origin and mechanisms of nondisjunction in human trisomy 21 that has accumulated during the last decade by using DNA polymorphism analysis. The first molecular correlate of nondisjunction in humans is altered recombination, meiosis I errors being associated with reduced recombination and maternal meiosis II errors with increased recombination between the nondisjoined chromosomes. Thus, virtually all maternal meiotic errors of chromosome 21 seem to be initiated in meiosis I. Advanced maternal age remains the only well documented risk factor for maternal meiotic nondisjunction, but there is, however, still a surprising lack of understanding of the basic mechanisms behind the maternal age effect.     

New insights into human nondisjunction of chromosome 21 in oocytes

Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors.     

Parental origin of chromosomes in Down's syndrome

Summary The number of 21 chromosomes of 15 individuals with Down's syndrome and their parents were examined in an attempt to determine the parental origin of the extra number 21 chromosome and the stage of meiosis at which nondisjunction occurred. Chromosomes were stained with quinacrine hydrochloride and photographed; serial prints were made ranging from underexposed to overexposed. Twelve of the 15 families (80%) were informative: nondisjunction occurred in maternal meiosis I in eight (66.7%) families, in paternal meiosis I in two (16.7%) families, and in paternal meiosis II in two (16.7%) families. The production of serial exposures of chromosomes at the time of printing proved to be a valuable method of enhancing slight differences in short arm and satellite structure of the number 21 chromosomes and thereby increasing the number of informative families.     

Origin of trisomy 21 in Down syndrome cases from a Spanish population registry

We have carried out a population-based study on the origin of the extra chromosome 21 in 38 families with Down syndrome (DS) offspring in El Vallès (Spain). From 1991 to 1994, a higher prevalence of DS (22.7/10000 live births, stillbirths and induced abortions) was found compared to the majority of EUROCAT registries. The distribution of trisomy 21 by origin was 88% maternal (90.6% meiosis I, 6.2% meiosis II, 3.1% maternal mosaicism), 5.6% paternal (50% meiosis I, 50% meiosis II) and 5.6% mitotic. The percentage of parental mosaicism was 2.7%. These percentages are similar to those previously reported. Recombination study revealed a maternal meiosis I genetic map of 32.68 cM (approximately one-half the length of the normal female map). Mean maternal age among non-recombinant cases involving MI errors was significantly lower (31.1 years) than among those cases showing one observable crossover (36.1 years) (P<0.05); this could support the hypothesis that 'achiasmate' chromosomes may be subject to aberrant segregation regardless of maternal age.     

Understanding the mechanism(s) of mosaic trisomy 21 by using DNA polymorphism analysis.

In order to investigate the mechanism(s) underlying mosaicism for trisomy 21, we genotyped 17 families with mosaic trisomy 21 probands, using 28 PCR-detectable DNA polymorphic markers that map in the pericentromeric region and long arm of chromosome 21. The percentage of cells with trisomy 21 in the probands'' blood lymphocytes was 6%-94%. There were two classes of autoradiographic results: In class I, a "third allele" of lower intensity was detected in the proband''s DNA for at least two chromosome 21 markers. The interpretation of this result was that the proband had inherited three chromosomes 21 after meiotic nondisjunction (NDJ) (trisomy 21 zygote) and subsequently lost one because of mitotic (somatic) error, the lost chromosome 21 being that with the lowest-intensity polymorphic allele. The parental origin and the meiotic stage of NDJ could also be determined. In class II, a "third allele" was never detected. In these cases, the mosaicism probably occurred either by a postzygotic, mitotic error in a normal zygote that followed a normal meiosis (class IIA mechanism); by premeiotic, mitotic NDJ yielding an aneusomic zygote after meiosis, and subsequent mitotic loss (class IIB mechanism); or by a meiosis II error with lack of crossover in the preceding meiosis I, followed by mitotic loss after fertilization (class IIC mechanism). Among class II mechanisms, the most likely is mechanism IIA, while IIC is the least likely. There were 10 cases of class I and 7 cases of class II results.(ABSTRACT TRUNCATED AT 250 WORDS)     

Trisomy of human chromosome 18: Molecular studies on parental origin and cell stage of nondisjunction

We investigated the parent and cell division of origin of the extra chromosome 18 in 62 aneuploids with a free trisomy 18 by using chromosome-18-specific pericentromeric short-sequence repeats. In 46 cases, DNA of patients was recovered from archival specimens, such as paraffin-embedded tissues and fixed chromosomal spreads. In 56 families, the supernumerary chromosome was maternal in origin; in six families, it was paternal. Among the 56 maternally derived aneuploids, we could exclude a postzygotic mitotic error in 52 cases. Among those in which the nondisjunction was attributable to an error at meiosis, 11 were the result of a meiosis I nondisjunction and 17 were caused by a meiosis II error. This result differs markedly from findings in acrocentric chromosomes where nondisjunction at maternal meiosis I predominates. Among the six paternally derived cases, two originated from a meiotic error, indicating that a nondisjunction in paternal meiosis is not as rare as previously suggested.Dedicated to Professor Dr. W. Gottschalk on the occasion of his 75th birthday     

Down syndrome due to de novo Robertsonian translocation t(14q;21q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal.

Down syndrome is rarely due to a de novo Robertsonian translocation t(14q;21q). DNA polymorphisms in eight families with Down syndrome due to de novo t(14q;21q) demonstrated maternal origin of the extra chromosome 21q in all cases. In seven nonmosaic cases the DNA markers showed crossing-over between two maternal chromosomes 21, and in one mosaic case no crossing-over was observed (this case was probably due to an early postzygotic nondisjunction). In the majority of cases (five of six informative families) the proximal marker D21S120 was reduced to homozygosity in the offspring with trisomy 21. The data can be best explained by chromatid translocation in meiosis I and by normal crossover and segregation in meiosis I and meiosis II.     

The meiotic stage of nondisjunction in trisomy 21: Determination by using DNA polymorphisms

We have studied DNA polymorphisms at loci in the pericentromeric region on the long arm of chromosome 21 in 200 families with trisomy 21, in order to determine the meiotic origin of nondisjunction. Maintenance of heterozygosity for parental markers in the individual with trisomy 21 was interpreted as resulting from a meiosis I error, while reduction to homozygosity was attributed to a meiosis II error. Nondisjunction was paternal in 9 cases and was maternal in 188 cases, as reported earlier. Among the 188 maternal cases, nondisjunction occurred in meiosis I in 128 cases and in meiosis II in 38 cases; in 22 cases the DNA markers used were uninformative. Therefore meiosis I was responsible for 77.1% and meiosis II for 22.9% of maternal nondisjunction. Among the 9 paternal nondisjunction cases the error occurred in meiosis I in 2 cases (22.2%) and in meiosis II in 7 (77.8%) cases. Since there was no significant difference in the distribution of maternal ages between maternal I error versus maternal II error, it is unlikely that an error at a particular of maternal ages between maternal I error versus maternal II error, it is unlikely that an error at a particular meiotic stage contributes significantly to the increasing incidence of Down syndrome with advancing maternal age. Although the DNA polymorphisms used were at loci which map close to the centromere, it is likely that rare errors in meiotic-origin assignments may have occurred because of a small number of crossovers between the markers and the centromere.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nondisjunction of human acrocentric chromosomes: studies of 432 trisomic fetuses and liveborns

The present report summarizes molecular studies on the parent and meiotic stage of origin of the additional chromosome in 432 fetuses or liveborns with an additional chromosome 13, 14, 15, 21, or 22. Our studies suggest that there is little variation in the origin of nondisjunction among the five acrocentric trisomies and that there is no association between the origin of nondisjunction and the likelihood of survival to term of the trisomic conceptus. The proportion of cases of paternal origin was similar among the five trisomies: 12% for trisomy 13, 17% for trisomy 14, 12% for trisomy 15, 9% for trisomy 21, and 11% for trisomy 22. The stage of nondisjunction was also similar among the five trisomies, with the majority of cases of maternal origin being due to nondisjunction at meiosis I, whereas for paternally derived cases, nondisjuction occurred primarily at meiosis II.     

Altered patterns of multiple recombinant events are associated with nondisjunction of chromosome 21

We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.     

Trisomy 21 (Down syndrome): studying nondisjunction and meiotic recombination by using cytogenetic and molecular polymorphisms that span chromosome 21.

By combining molecular and cytogenetic techniques, we demonstrated the feasibility and desirability of a comprehensive approach to analysis of nondisjunction for chromosome 21. We analyzed the parental origin and stage of meiotic errors resulting in trisomy 21 in each of five families by successfully using cytogenetic heteromorphisms and DNA polymorphisms. The 16 DNA fragments used to detect polymorphisms spanned the length of the long arm and detected recombinational events on nondisjoined chromosomes in both maternal meiosis I and maternal meiosis II errors. The meiotic stage at which errors occurred was determined by sandwiching the centromere between cytogenetic heteromorphisms on 21p and an informative haplotype constructed using two polymorphic DNA probes that map to 21q just below the centromere. This study illustrates the necessity of combining cytogenetic polymorphisms on 21p with DNA polymorphisms spanning 21q to determine (1) the source and stage of meiotic errors that lead to trisomy 21 and (2) whether an association exists between nondisjunction and meiotic recombination.     

Origin of acrocentric trisomies in spontaneous abortuses

Summary A total of 33 spontaneous abortuses with various acrocentric trisomies were studied for the origin of the extra chromosomes using Q- and R-band polymorphisms as markers. Eleven trisomic abortuses were informative: nine trisomic abortuses (one with trisomy 13, three with trisomy 21, and five with trisomy 22 including one with a 46,XX/47,XX,+22 mosaicism) originated at maternal first meiosis; a 21-trisomic abortus resulted from an error at maternal second meiosis (or first mitosis); and a 13-trisomic abortus was of maternal first or second meiotic origin. The abortus with mosaic trisomy 22 started as a 22-trisomic zygote resulting from an error at maternal first meiosis, followed by a mitotic (in vivo or in vitro) loss of the paternally derived chromosome 22.     

Molecular studies of trisomy 18.

We have determined the parental origin of 50 cases of trisomy 18. In 48 cases the additional chromosome was maternal in origin, and in 2 cases it was paternal in origin. Seven cases, including both those with an additional paternal chromosome, appeared to be the result of postzygotic error. In contrast to the situation in nondisjunction involving chromosomes 21 and X, there was no evidence for nullochiasmate nondisjunction.     

Formation of supernumerary euchromatic short arm isochromosomes: parent and cell stage of origin in new cases and review of the literature.

In order to get insight in the formation of isochromosomes we analysed different supernumerary euchromatic short arm isochromosomes for the parent and cell stage of origin. After cytogenetic detection and confirmation by fluorescence-in-situ hybridization we performed short tandem repeat typing in a child with i(9p), three with i(12p) and three with i(18p). The extra chromosomes were monocentric in each case, the i(9p) and i(12p) constitutions were found in mosaic with normal cell lines. Our results and those of other groups indicate a strong role of maternal meiosis in isochromosome formation: in one i(8p), 4 out of 5 i(9p), 7 out of 12 i(12p) and 18 out of 23 i(18p) families a maternal meiotic nondisjunction had occurred prior to the centromere misdivision. For chromosome 18, the majority of isochromosomes originated from a maternal meiosis II error (16/18). For the other tetrasomic constitutions the isochromosomes could be delineated from paternal as well as from maternal origin, the short tandem repeat typing patterns being consistent with meiotic or mitotic cell stages of formation. Thus, independently of the chromosomal origin, in the majority of cases with additional euchromatic isochromosomes maternal meiosis nondisjunction is the initial step followed by centromeric misdivision. Postzygotic nondisjunction as suggested previously due to mosaics observed in tetrasomies 9p and 12p seems to be of minor importance. The observed origin of isochromosomes 18 corresponds to that of trisomy 18, where the majority of cases can be delineated from maternal meiosis II errors.     

Variation in alphoid DNA size and trisomy 21: a possible cause of nondisjunction

The cause of nondisjunction of chromosome 21 remains largely unknown. In the present report, we investigate the hypothesis that variation in alphoid DNA size has a role in trisomy formation. Pulsed-field gel electrophoresis was used to examine the chromosome 21 alphoid DNA array lengths in 23 families (all of Northern European ancestry) with an affected child with trisomy 21 in whom the parental and meiotic origin of nondisjunction had been determined as maternal meiosis I, and in 38 controls. Initially, the combined alphoid size of both chromosome 21 homologues was assessed. This indicated an association between small combined alphoid size and maternal meiosis I nondisjunction. Moreover, in a subset of the families under study (n=12), it was possible to study the alpha21-I size of individual chromosome 21 homologues (simple alphoid size); this provided further evidence that the risk for nondisjunction is related to the size of the alphoid array of one of the two chromosome 21 homologues being small.     

Origin of extra chromosome in Patau syndrome

Summary Five live-born infants with Patau syndrome were studied for the nondisjunctional origin of the extra chromosome. Transmission modes of chromosomes 13 from parents to a child were determined using both QFQ- and RFA-heteromorphims as markers, and the origin was ascertained in all of the patients. The extra chromosome had originated in nondisjunction at the maternal first meiotic division in two patients, at the maternal second meiosis in other two, and at the paternal first meiosis in the remaining one.Summarizing the results of the present study, together with those of the previous studies on a liveborn and abortuses with trisomy 13, nondisjunction at the maternal and the paternal meiosis occurred in this trisomy in the ratio of 14:3. This ratio is not statistically different from that inferred from the previous studies for Down syndrome. These findings suggest that there may be a fundamental mechanism common to the occurrence of nondisjunction in the acrocentric trisomies.     

Meiosis in four trisomic and one double trisomic males of the newt Pleurodeles waltlii

In the newt Pleurodeles waltlii, meiosis was studied in four trisomic and one double trisomic males. Study of first prophase shows that trivalent frequencies and trivalent configurations are correlated with chromosome length; moreover, trivalent configurations indicate that long chromosomes have multiple points of initiation of synapsis whereas two points might be adequate to secure synapsis of short chromosomes. From the study of metaphase II it appears that the extra chromosomes segregate in half of the spermatocytes II. Some abnormal spermatocytes, resulting from nondisjunction of chromosomes at mitosis or at first division of meiosis, or from precocious division of chromosomes at first division of meiosis were observed. In the male double trisomic meiosis fails at anaphase of second division; this accounts for the sterility of the individual.