Parental origin and meiotic stage of non-disjunction in 139 cases of trisomy 21

The parental origin and the meiotic stage of non-disjunction have been determined in 139 Down syndrome patients with regular trisomy 21 and in their parents through the analysis of DNA polymorphism. The meiotic error is maternal in 91.60% cases and paternal in 8.39% of cases. Of the maternal cases, 72.41% were due to meiosis I errors (MMI) and 27.58% were due to meiosis II errors (MMII). Of the paternal cases, 45.45% were due to meiosis I (PMI) and 54.54% were due to meiosis II (PMII). The mean maternal ages were 31.6 +/- 5.3 (+/- SD) years in errors from MMI, 32.3 +/- 6.4 years in errors from MMII, 31.4 +/- 4.6 years in errors from PMI and 29.5 +/- 2.7 years in errors from PMII. No significant statistical differences were observed between maternal and paternal errors, further supporting the presence of a constant chromosome 21 non-disjunction error type.     

Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects

We examined the association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error. We analyzed data from two population-based, case–control studies: Atlanta Down Syndrome Project (1989–1999) and National Down Syndrome Project (2001–2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four primary findings. First, the significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the egg; the association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers of controls, mothers of infants with trisomy 21 due to MI nondisjunction were 8.5 times more likely to be ≥40 years old than 20–24 years old at the birth of the index case (95% CI = 5.6–12.9). Where nondisjunction occurred in MII, mothers were 15.1 times more likely to be ≥40 years (95% CI = 8.4–27.3). Third, the ratio of MI to MII errors differed by maternal age. The ratio was lower among women <19 years of age and those ≥40 years (2.1, 2.3, respectively) and higher in the middle age group (3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal nondisjunction. This study emphasizes the complex association between advanced maternal age and nondisjunction of chromosome 21 during oogenesis. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.     

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 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.     

Trisomy 18: studies of the parent and cell division of origin and the effect of aberrant recombination on nondisjunction.

We have studied the mechanism of origin of 63 cases of trisomy 18. In 2 the additional chromosome was paternal in origin, and in the remaining 61 it was maternal in origin. Both paternal cases were attributable to a postzygotic mitotic (PZM) error. Among the 54 maternal cases for which the cell division of error was established, only 16 were attributable to an error at the first meiotic division (mat MI), whereas no fewer than 35 were due to an error at the second meiotic division (mat MII), the remaining 3 being the result of a PZM error involving the maternal chromosome 18. A standard map of chromosome 18 was constructed and compared with the nondisjunctional map. Approximately one-third of the mat MI errors were associated with complete absence of recombination, whereas in the remaining two-thirds and in all the mat MII errors recombination in the nondisjoined chromosomes appeared to be normal. All the maternal errors were associated with an increased maternal age, although this reached significance only for the mat MII category of nondisjunction. Our observations on chromosome 18 are compared with those on other chromosomes for which there are comparable data.     

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.     

QF-PCR examination of parental and meiotic origin of trisomy 21 in Central and Eastern Europe.

Study of parental/meiotic origin of free trisomy 21 in nuclear families from Russia (70 cases), Ukraine (32 cases), and 22 from Germany revealed maternal nondisjunction in 77.3% (Germany), 93.8% (Ukraine), and 91.4% (Russia), paternal origin in 13.6%, 6.2%, and 8.6%, respectively. Maternal meiosis I errors were found in 84.4% (Ukraine), 77.1% (Russia), paternal origin in 3.1% (Ukraine), 2.9% (Russia). Maternal meiosis II errors occurred in 9.4% and 14.3% and paternal in 3.1% and 5.7% in Ukraine and Russia, respectively. No significant differences were found in maternal/paternal origin among Ukraine, Russia, Germany, and published data from other European regions.     

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)     

Non-disjunction of chromosome 21, alphoid DNA variation, and sociogenetic features of Down syndrome

The analysis of non-disjunction of chromosome 21 and alphoid DNA variation by using cytogenetic and molecular cytogenetic techniques (quantitative fluorescence in situ hybridization) in 74 nuclear families was performed. The establishment of possible correlation between alphoid DNA variation, parental age, environmental effects, and non-disjunction of chromosome 21 was made. The efficiency of techniques applied was found to be 92% (68 from 74 cases). Maternal non-disjunction wasfound in 58 cases (86%) and paternal non-disjunction - in 7 cases (10%). Post-zygotic mitotic non-disjunction was determined in 2 cases (3%) and one case was associated with Robertsonian translocation 46,XX,der(21;21)(q10;q10), +21. Maternal meiosis I errors were found in 43 cases (64%) and maternal meiosis II errors--in 15 cases (22%). Paternal meiosis I errors occurred in 2 cases (3%) and paternal meiosis I errors--in 5 cases (7%). The lack of the correlation between alphoid DNA variation and non-disjunction of chromosome 21 was established. Sociogenetic analysis revealed the association of intensive drug therapy of infectious diseases during the periconceptual period and maternal meiotic non-disjunction of chromosome 21. The correlation between non-disjunction of chromosome 21 and increased parental age as well as exposure to irradiation, alcohol, tobacco, mutagenic substances was not found. The possible relevance of data obtained to the subsequent studies of chromosome 21 non-disjunction is discussed.     

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.     

Parental origin of the extra chromosome in Down's syndrome

Summary Chromosome 21 fluorescent heteromorphisms were studied in 42 patients with Down's syndrome, their parents and their siblings. Included in this number are two instances of an aunt and niece affected with trisomy 21, and one of affected siblings. One case has a de novo 21/21 translocation. Blood group, red cell and serum protein markers were also studied for linkage, gene exclusions, associations, and paternity testing. Thirty-one of the trisomy 21 cases were informative for parental origin of the extra chromosome and for stage of meiosis. The non-disjunctional event was of maternal origin in 24; 23 occurred in meiosis I, 1 in meiosis II. Seven were of paternal origin; 5 in meiosis I, and 2 in meiosis II. The translocation case was of paternal origin. A literature search revealed a total of 98 cases informative for the parent of origin of the extra chromosome, of >347 families tested. In addition, 3 de novo translocation cases, of 7 tested, were informative. The data suggest that most cases result from an error in the first meiotic division in the mother, but that a significant proportion are paternal in origin.     

Down syndrome and maternal age: the effect of erroneous assignment of parental origin.

It is tempting to assume that the maternal age effect in trisomy 21 is confined to cases arising from errors of maternal gametogenesis. However, it has been suggested that this hypothesis is incompatible with the results of studies, based on the subjective assessment of chromosome polymorphisms, of the parental origin of the additional chromosome. Contrary to the hypothesis, these studies appear to indicate that the ratio of maternal to paternal errors does not depend significantly on maternal age. I show here that the hypothesis need not be rejected if the proportion of published parental assignments that are incorrect is greater than or equal to 8%, a figure regarded as realistic by some experienced cytogeneticists.     

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.     

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.     

Parental origin of chromosome abnormalities in spontaneous abortions

Summary Tissue cultures were initiated from 130 spontaneous abortion specimens and 81 were successfully karyotyped. Chromosome abnormalities were found in 50 cases: 12 with XO, 27 with trisomy, 6 with triploidy, 1 with tetraploidy and 4 others. The parental origin was determined in 11 cases of trisomy for an acrocentric chromosome. Two cases were uninformative while 9 non-disjunctions were determined and occurred during meiosis I: 7 were maternal and 2 paternal (both with trisomy 21). Three out of 7 cases with trisomy 16 were informative and resulted from a divisional error during the first meiotic division in the mother. All cases of triploidy were informative. They resulted from non-reduction during meiosis I in the mother (2) or dispermy (4).     

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 the aetiology of trisomy 8 in spontaneous abortions and the liveborn population

We have determined the parental origin in eight cases of constitutional trisomy 8. In all four cases of spontaneous abortion, the additional chromosome was maternal in origin and there was evidence for nullichiasmate meiosis I occurring in the genesis of this trisomy. In contrast, all four cases of liveborn trisomy 8 appear to have arisen by a mechanism consistent with the post-zygotic mitotic gain of the additional chromosome.     

Predictors of trisomy 21 in the offspring of older and younger women

BACKGROUND: Advanced maternal age is the only well‐established risk factor for trisomy 21, yet the majority of affected individuals are born to younger women. To identify factors associated with the risk of trisomy 21 in the offspring of younger and older women, we analyzed data for cases with trisomy 21 from the Texas Birth Defects Registry for 1999 to 2007. METHODS: Data were analyzed separately for younger (i.e., <35 years of age at delivery; n = 2306) and older (i.e., ≥35 years of age at delivery; n = 1811) women using Poisson regression. RESULTS: After adjustment for maternal age and several other covariates, the prevalence of trisomy 21 in the offspring of women in both maternal age groups was higher in male than in female infants and in offspring of women who were Hispanic (compared with non‐Hispanic white women) or who had at least one previous liveborn child compared to those with none. In the offspring of older women only, the prevalence of trisomy 21 was also significantly higher when the father was 20to 24 years old (compared with 25 to 29 years old; adjusted prevalence ratio [aPR], 2.27; 95% confidence interval [CI], 1.47–3.49) and Hispanic (compared with non‐Hispanic white; aPR, 1.34; 95% CI, 1.13–1.58) and among women with less than a high school education (compared with greater than high school). CONCLUSIONS: This study identified several factors, in addition to maternal age, that were associated with trisomy 21 risk. In general, these factors were similar for both maternal age groups, although paternal characteristics were significantly associated with risk of trisomy 21 only in offspring of older women. Birth Defects Research (Part A), 2012. © 2011 Wiley Periodicals, Inc.     

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)     

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.