Origin of the extra chromosome in trisomy 18

Summary The parental origin of an extra chromosome in five patients with trisomy 18 was traced using a restriction fragment length polymorphism (RFLP) of the human prealbumin (PA) gene, localized to 18p11.1–q12.1, as a genetic marker. MspI digests of the genomic DNAs of the five patients, their parents and normal controls were hybridized with the PAcDNA. Densitometric analysis on the gene dose of the polymorphic fragments of these patients revealed that three had originated from a maternal meiotic error. The other two patients were uninformative for the parental origin of trisomy 18. Our results indicate that nondisjunctional errors leading to trisomy 18 may occur predominantly at the maternal meiosis, consistent with the results of previous studies on the parental origin of trisomies 21 and 13.     

Maternal and paternal origin of extra chromosome in trisomy 21

Summary Fluorescence markers were studied in 40 patients with Down's syndrome and their parents. In 11 cases maternal and in 5 cases paternal non-disjunction could be shown. The disjunctional event occurred in the first meiotic division in 5 maternal and in 2 paternal cases. A second division failure was found in 4 maternal and 2 paternal cases. In 3 cases the failure could either be of first or second meiotic division origin.     

Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21

Trisomy 21 (Down syndrome) is one of the most common chromosomal abnormalities. Of cases of free trisomy 21 causing Down syndrome, about 95% result from nondisjunction during meiosis, and about 5% are due to mitotic errors in somatic cells. Previous studies using DNA polymorphisms of chromosome 21 showed that paternal origin of trisomy 21 occurred in only 6.7% of cases. However, these studies were conducted in liveborn trisomy 21-affected infants, and the possible impact of fetal death was not taken into account. Using nine distinct DNA polymorphisms, we tested 110 families with a prenatally diagnosed trisomy 21 fetus. Of the 102 informative cases, parental origin was maternal in 91 cases (89.2%) and paternal in 11 (10.8%). This percentage differs significantly from the 7.0% observed in previous studies (P<0.001). In order to test the influence of genomic parental imprinting, we determined the origin of the extra chromosome 21 in relation to different factors: advanced maternal age, maternal serum human chorionic gonadotropin (hormone of placental origin), severity of the disease, gestational age at diagnosis and fetal gender. We found that the increased frequency of paternal origin of nondisjunction in trisomy 21-affected fetuses cannot obviously be explained by factors leading to selective loss of paternal origin fetuses.     

Origin of the extra chromosome No. 21 in Down's syndrome

Summary A No. 15 chromosome with a short arm longer than usual is observed in two phenotypically normal brothers. This chromosome appears to have no visible satellite, shows no N-band staining, and is never involved in satellite association. These results have led us to the conclusion that this chromosome lacks the nucleolus organizer region.     

Parental origin of the extra chromosome in trisomy 18.

The parental origin of the supernumerary chromosome 18 was investigated by RFLP analysis in 23 individuals with Edwards syndrome. All families were studied with the DNA probe pERT-25, which recognizes a locus of highly polymorphic tandemly repeated DNA sequences on chromosome 18. The extra chromosome was found to be of maternal origin in 19 patients (95%), of paternal origin in one patient (5%), and indeterminate in three patients. In one of the three indeterminate cases, a mosaic, an apparent recombination event had taken place within the pERT-25 locus. The overall high degree of informativeness of pERT-25 illustrates the power of a chromosome-specific variable-number tandem repeat probe (VNTR) in parental origin studies of aneuploidy.     

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.     

Pure trisomy 19p syndrome in an infant with an extra ring chromosome

We report a 12-month-old infant evaluated for severe hypotonia, psychomotor retardation, and facial dysmorphisms, including round face, high prominent forehead, downward slanted palpebral fissures, hypertelorism, short nose, chubby cheeks, long philtrum, anteverted lower lip, low-set asymmetric and dysmorphic ears. Karyotype analysis disclosed an extra mosaic ring chromosome, which included the whole 19p arm. Four additional patients with supernumerary ring 19 chromosomes have been reported, but none of them had pure trisomy 19p.     

Retrospective study of the parental origin of the extra chromosome in trisomy 18 (Edwards syndrome)

The parental origin of the extra chromosome in trisomy 18 was traced in 30 informative families using highly polymorphic (CA) repeats mapped on the long arm of chromosome 18. Proband DNA was recovered from slides of chromosome preparations in 28 cases and from paraffin-embedded tissues in two cases. The extra chromosome was found to be of maternal origin in 26 cases (86.7%), and paternal origin in 4 cases (13.3%).     

Meiotic chromosome pairing in fetal oocytes of trisomy 21 human females

The influence of trisomy on meiotic chromosome association and synapsis was studied in oocytes of two trisomy 21 fetuses. The patterns of association of the three chromosomes 21 were determined by analysis of late zygotene to early diplotene fetal oocytes after immunofluorescent staining of synaptonemal complexes. The identity of chromosome 21 was confirmed using FISH with either a whole chromosome 21 paint or an alpha-satellite DNA repeat probe. In both fetuses, a wide variety of configurations was present at pachytene. The most common configurations were a trivalent (35.5% and 51.6% of analyzable cells) and a bivalent plus univalent (62.9% and 45.2%). These different frequencies between the fetuses were not significant. Trivalents showed either triple synapsis or double synapsis with pairing-partner switches. The extent of triple synapsis varied from a short segment, either terminal or interstitial, to the whole chromosome length. Through use of immunofluorescent staining of the centromeres, we identified novel types of abnormal chromosome behavior in trisomy 21 fetal oocytes. Thus, we found that 6/41 trivalents had one of the chromosomes associated "out of register," i.e., in a nonhomologous fashion, with its two homologs. Likewise, we found three cells with bivalent plus univalent configurations, in which the univalent showed self-synapsis. The presence of three copies of chromosome 21 therefore results not only in the formation of complex and highly variable synaptic associations but also causes a significant increase in the occurrence of nonhomologous synapsis in human fetal oocytes.     

Spatial organization of chromosome territories in the interphase nucleus of trisomy 21 cells

In the interphase cell nucleus, chromosomes adopt a conserved and non-random arrangement in subnuclear domains called chromosome territories (CTs). Whereas chromosome translocation can affect CT organization in tumor cell nuclei, little is known about how aneuploidies can impact CT organization. Here, we performed 3D-FISH on control and trisomic 21 nuclei to track the patterning of chromosome territories, focusing on the radial distribution of trisomic HSA21 as well as 11 disomic chromosomes. We have established an experimental design based on cultured chorionic villus cells which keep their original mesenchymal features including a characteristic ellipsoid nuclear morphology and a radial CT distribution that correlates with chromosome size. Our study suggests that in trisomy 21 nuclei, the extra HSA21 induces a shift of HSA1 and HSA3 CTs out toward a more peripheral position in nuclear space and a higher compaction of HSA1 and HSA17 CTs. We posit that the presence of a supernumerary chromosome 21 alters chromosome compaction and results in displacement of other chromosome territories from their usual nuclear position.     

Submicroscopic duplication of chromosome 21 and trisomy 21 phenotype (Down syndrome)

Summary A patient with the phenotype of trisomy 21 (Down syndrome) was found to have a normal karyotype in blood lymphocytes and fibroblasts. Assessment of the chromosome 21 markers SOD1, CBS, ETS2, D21S11, and BCEI showed partial trisomy by duplication of a chromosome segment carrying the SOD1, CBS, and ETS2 loci and flanked by the BCEI and D21S11 loci, which are not duplicated. This submicroscopic duplication at the interface of 21q21 and 21q22.1 reduces to about 2000–3000kb the critical segment the trisomy of which is responsible for the phenotype of trisomy 21.     

A satellited Yq chromosome associated with trisomy 21 and an inversion of chromosome 9

Summary A case of satellited Yq, inverted 9 and trisomy 21 is described. The clinical features are typical of those found in Down's syndrome.     

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.     

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.     

Increased methotrexate-induced chromosome breakage in patients with free trisomy 21 and their parents

Summary Increased susceptibility of chromosomes from peripheral blood lymphocytes to the antimetabolite methotrexate (2×10^-6 M) has been found in patients with free trisomy 21 and their parents (N=14). The level of induced chromatid and chromosome breaks is lowest in normal controls intermediate in patients' mothers and fathers, and highest in trisomy 21 patients. The findings are viewed as a special type of cytogenetic polymorphism or as a defective chromosomal infrastructure, also in the parents of trisomic children.Dedicated to Professor Dr. H.A. Freye, Halle/Saale, in honor of his 65th birthday     

Maternally transmitted extra ring(21) chromosome in a boy with Down's syndrome

Summary An 11-month-old boy with typical Down's syndrome is presented. His karyotype was 47,XY,+r(21); the erythrocyte superoxide dismutase-1 (SOD-1) activity was elevated. His phenotypically normal mother showed 46,XX,r(21) karyotype and normal SOD-1 activity. Analysis of chromosomal heteromorphism revealed that in addition to the ring, a normal chromosome 21 was transmitted from the mother.     

Sex ratio in normal and disomic sperm: evidence that the extra chromosome 21 preferentially segregates with the Y chromosome.

In humans, deviations from a 1:1 male:female ratio have been identified in both chromosomally normal and trisomic live births: among normal newborns there is a slight excess of males, among trisomy 18 live borns a large excess of females, and among trisomy 21 live borns an excess of males. These differences could arise from differential production of or fertilization by Y- or X-bearing sperm or from selection against male or female conceptions. To examine the proportion of Y- and X-bearing sperm in normal sperm and in sperm disomic for chromosomes 18 or 21, we used three-color FISH (to the X and Y and either chromosome 18 or chromosome 21) to analyze >300,000 sperm from 24 men. In apparently normal sperm, the sex ratio was nearly 1:1 (148,074 Y-bearing to 148,657 X-bearing sperm), and the value was not affected by the age of the donor. Certain of the donors, however, had significant excesses of Y- or X-bearing sperm. In disomy 18 sperm, there were virtually identical numbers of Y- and X-bearing sperm; thus, the excess of females in trisomy 18 presumably is due to selection against male trisomic conceptions. In contrast, we observed 69 Y-bearing and 44 X-bearing sperm disomic for chromosome 21. This is consistent with previous molecular studies, which have identified an excess of males among paternally derived cases of trisomy 21, and suggests that some of the excess of males among Down syndrome individuals is attributable to a nondisjunctional mechanism in which the extra chromosome 21 preferentially segregates with the Y chromosome.     

Partial trisomy 21

Summary Cytogenetic analysis of a 6-year-old girl with moderate mental retardation revealed 46 chromosomes with a tandem translocation (21;21) resulting in a partial trisomy 21. Only the terminal band 21q22 was not in triplicate. G-, Q-, R-, and C-banding techniques and silver nitrate staining of the nucleolus organizer regions (NORs) were used to identify this chromosome fully.The phenotype of the patient was not typical for Down's syndrome, providing additional evidence that trisomy of band 21q22 is pathogenetic for the phenotype of Down's syndrome. This is also a new example in human pathology of a stable dicentric chromosome in which one of the centromeric constrictions appears to be nonfunctional.