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Background: We hypothesized that trisomy arises as a function of the size of the oocyte pool, with risk increased among women with diminished pools. Diminished pools may cause primary ovarian failure, which has been associated with premutation and intermediate CGG repeat length at the Fragile X mental retardation (FMR1) locus. Thus, we hypothesized that the risk of trisomic pregnancy is increased among women with intermediate CGG repeat length on the FMR1 gene., Methods: The analysis drew on data from two hospital-based case-control studies. We compared 207 women with trisomic spontaneous abortions (SAs) to three comparison groups: 82 women with other chromosomally abnormal SAs, 99 women with chromosomally normal SAs and 537 women with live births (LBs), age matched to women with SAs. We defined the length of the CGG repeat in four ways: the biallelic mean, the genotypic mean, the length on allele 2 and the length on allele 1. We analyzed CGG repeat length as a categorical variable. All analyses were adjusted for site, age and ethnicity., Results: CGG repeat length did not differ significantly between women with trisomic SAs and any of the three comparison groups. For the biallelic mean, the adjusted odds ratio relating trisomy (versus LB controls) to the highest category (35.5-59.5 repeats) versus the modal category (26.5-30.0 repeats) was 1.5 (95% confidence interval (CI): 0.7, 3.1). Comparisons with the two SA control groups also showed increased odds of more repeats among trisomy cases. Results were similar when repeat length was defined by the genotypic mean or by the repeat length on allele 2. For allele 1, the odds of short (9-19) repeat length were lower, but not significantly so, for trisomy cases compared with LB controls. Excluding women with premutations (n= 2) from the analysis yielded an adjusted odds ratio of 1.4 (95% CI: 0.7, 2.9) for the biallelic mean., Conclusions: Our data are equivocal. The direction of associations is consistent with the hypothesis that repeat length in the intermediate range is associated with trisomy. However, differences between the trisomy cases and the comparison groups are neither large nor statistically significant. Our data rule out odds ratios larger than about 3.

Background: Some studies, but not all, support the hypothesis that trisomy frequency is related to the size of the oocyte pool, with the risk increased for women with fewer oocytes (older ovarian age). We tested this hypothesis by comparing hormonal indicators of ovarian age among women who had trisomic pregnancy losses with indicators among women with non-trisomic losses or chromosomally normal births. The three primary indicators of advanced ovarian age were low level of anti-Müllerian hormone (AMH), high level of follicle-stimulating hormone (FSH) and low level of inhibin B., Methods: The analysis drew on data from two hospital-based case-control studies. Data were analyzed separately and the evidence from the two sites was combined. We compared 159 women with trisomic pregnancy losses to three comparison groups: 60 women with other chromosomally abnormal losses, 79 women with chromosomally normal losses and 344 women with live births (LBs) age-matched to women with losses. We analyzed the hormone measures as continuous and as categorical variables. All analyses adjust for age in single years, day of blood draw, interval in storage and site., Results: AMH and inhibin B did not differ between women with trisomic losses and any of the three comparison groups. Mean ln(FSH) was 0.137 units (95% confidence interval (CI): 0.055, 0.219) higher for trisomy cases compared with LB controls; it was also higher, though not significantly so, for trisomy cases compared with women with other chromosomally abnormal losses or chromosomally normal losses. The adjusted odds ratio in relation to high FSH (≥ 10 mIU/ml) was significantly increased for trisomy cases versus LB controls (adjusted odds ratio (OR): 3.8, 95% CI: 1.6, 8.9)., Conclusions: The association of trisomy with elevated FSH is compatible with the oocyte pool hypothesis, whereas the absence of an association with AMH is not. Alternative interpretations are considered, including the possibility that elevated FSH may disrupt meiotic processes or allow recruitment of abnormal follicles.

Several studies suggest that highly skewed X chromosome inactivation (HSXI) is associated with recurrent spontaneous abortion. We hypothesized that this association reflects an increased rate of trisomic conceptions due to anomalies on the X chromosome that lead both to HSXI and to a diminished oocyte pool. We compared the distribution of X chromosome inactivation (XCI) skewing percentages (range: 50%-100%) among women with spontaneous abortions in four karyotype groups-trisomy (n = 154), chromosomally normal male (n = 43), chromosomally normal female (n = 38), nontrisomic chromosomally abnormal (n = 61)-to the distribution for age-matched controls with chromosomally normal births (n = 388). In secondary analyses, we subdivided the nontrisomic chromosomally abnormal group, divided trisomies by chromosome, and classified women by reproductive history. Our data support neither an association of HSXI with all trisomies nor an association of HSXI with chromosomally normal male spontaneous abortions. We also find no association between HSXI and recurrent abortion (n = 45).

Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8-16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.

Few reliable data exist concerning the recurrence risk for individual trisomies or the risk for recurrence of trisomy for a different chromosome. We collected records from two sources: (1) prenatal diagnoses performed at the Hopital Sainte-Justine in Montreal and (2) karyotype analyses performed at Genzyme. Using the standardized morbidity ratio (SMR), we compared the observed number of trisomies at prenatal diagnosis with the expected numbers, given maternal age-specific rates (by single year). SMRs were calculated both for recurrence of the same trisomy (homotrisomy) and of a different trisomy (heterotrisomy). After all cases with an index trisomy 21 were combined, the SMR for homotrisomy was 2.4 (90% CI 1.6-3.4; P=.0005). For women with both the index trisomy and subsequent prenatal diagnosis at age <30 years, the SMR was 8.0; it was 2.1 for women with both pregnancies at age >/=30 years. For the other index viable trisomies (13, 18, XXX, and XXY) combined, the SMR for homotrisomy was 2.5 (90% CI 0.7-8.0). For heterotrisomy, the SMR after an index trisomy 21 was 2.3 (90% CI 1.5-3.8, P=.0007); the SMR did not vary with maternal age at the first trisomy. When all cases with index viable trisomies were combined, the SMR for heterotrisomy was 1.6 (90% CI 1.1-2.4; P=.04). For prenatal diagnoses following a nonviable trisomy diagnosed in a spontaneous abortion (from Genzyme data only), the SMR for a viable trisomy was 1.8 (90% CI 1.1-3.0; P=.04). The significantly increased risk for heterotrisomy supports the hypothesis that some women have a risk for nondisjunction higher than do others of the same age.

Background: We tested the hypothesis that trisomy risk is increased for women with fewer oocytes (older ovarian age) than other women of the same chronological age., Methods: Our study compared three indicators of ovarian age-number of antral follicles, level of dimeric inhibin B, level of FSH-among women who had trisomic pregnancy losses (n = 54) with those among women who had other losses (24 with other chromosomally abnormal loses, 21 with chromosomally normal losses) or who had chromosomally normal births (n = 65)., Results: Ovarian age indicators did not differ between women with trisomic spontaneous abortions and the three comparison groups. Compared with live birth controls, adjusting for chronological age, we estimate that, on average, among trisomy cases the geometric means of 1 + follicle count, inhibin B and FSH are about 7.5% higher, 16.6% higher and 5.5% lower, respectively, with all 95% confidence intervals including zero. The sample size was sufficient to detect moderate differences (0.52 standard errors of regression) between trisomy cases and live birth controls., Conclusions: Although our data do not support our hypothesis, they leave open the possibility that changes in follicular development unrelated to the size of the oocyte pool influence abnormal chromosome segregation.

We present a female infant with mild dysmorphic features and congenital heart defect: hypoplastic left heart with aortic atresia and hypoplastic aortic arch, ventricular septal defect, and a nonrestrictive atrial communication. Chromosome analysis showed an unbalanced translocation that contained additional material from 4q translocated onto 21q. This resulted in partial trisomy 4 and monosomy for the 21q telomeric region. The derivative chromosome was characterized using G-banding, M-FISH, and whole chromosome painting. The karyotype was described as 46,XX,der(21)t(4;21)(q25;q22.3).ish(wcp4+;wcp21+). Additional analyses with FISH probes specific for 21q 22.3, 21q22.2, 21q21.1, and 21q11.2 did not indicate any chromosome 21 duplication within the derivative chromosome 21. Monosomy for the telomeric portion of 21q was demonstrated using a tel 21q probe (Oncor). The patient underwent stage 1 Norwood procedure to manage her heart defect. Poor feeding and failure to thrive complicated the postsurgical period. The child subsequently underwent funduplication and feeding tube placement, and at 4.5 months of age presented with microcephaly and developmental delay. Hypoplastic left heart was previously reported with increased frequency in relatively common numeric chromosomal aberrations, such as monosomy X, trisomies 21, 18, and 13, and in various structural chromosomal defects. Our report presents new evidence for the co-occurrence of hypoplastic left heart with a duplicated portion of chromosome 4 distal to 4q25. In addition, monosomy for the telomeric region of chromosome 21 may have implications in the phenotype., (Copyright 2001 Wiley-Liss, Inc.)

We tested the hypothesis that the connection between advanced maternal age and autosomal trisomy reflects the diminution of the oocyte pool with age. Because menopause occurs when the number of oocytes falls below some threshold, our hypothesis is that menopause occurs at an earlier age among women with trisomic pregnancies than it does among women with chromosomally normal pregnancies. To determine their menstrual status, we interviewed women from our previous study of karyotyped spontaneous abortions who, in 1993, were age >/=44 years. Premenopausal women completed interviews every 4-5 mo, until menopause or until the study ended in 1997. The primary analyses compare 111 women whose index pregnancy was a trisomic spontaneous abortion with two groups: women whose index pregnancy was a chromosomally normal loss (n=157) and women whose index pregnancy was a chromosomally normal birth (n=226). We used a parametric logistic survival analysis to compare median ages at menopause. The estimated median age at menopause was 0.96 years earlier (95% confidence interval -0.18 to 2.10) among women with trisomic losses than it was among women with chromosomally normal losses and chromosomally normal births combined. Results were unaltered by adjustment for education, ethnicity, and cigarette smoking. Our results support the hypothesis that trisomy risk is increased with decreased numbers of oocytes. Decreased numbers may indicate accelerated oocyte atresia or fewer oocytes formed during fetal development.

A normal balanced chromosome 5 translocation carrier (5:14) (p14.1; q32.3) produced one offspring with a 5p deletion syndrome (cri du chat syndrome) and two with a partial trisomy (one with schizophrenia and the other with refractory epilepsy). We had hypothesized that the translocation might be complex and involve 5q, overlapping with a schizophrenia associated area described by Bassett et al., (1988). Cytogenetic study, however, indicated that there was no overlap in the involved chromosome 5 trisomy for this individual with schizophrenia and the trisomic region previously described. The probands with the trisomy and the cytogenetic findings are described in this report. Alternative interpretations are suggested to explain the association of schizophrenia and chromosomal abnormalities.

The relationship of paternal age to specific types of trisomy and to chromosomally normal loss was investigated in data drawn from a case-control study of spontaneous abortions. Differences in paternal age between karyotype groups and controls delivering after 28 weeks gestation were tested using an urn model analysis which adjusted, by regression, for maternal age and, by stratification, for the effects of design variables (payment status, phase of study) and demographic factors (language, ethnicity). The magnitude of paternal age differences was estimated using least squares regression analysis. For chromosomally normal cases there was no association with paternal age. Among the fourteen trisomy categories examined, four (7, 9, 18, 21) showed increased paternal age (greater than or equal to 1 year above expectation), three (13, 20, 22) showed decreased paternal age and the rest, including the most common, trisomy 16, showed negligible differences. Only the association with trisomy 22 was statistically significant (P = 0.012), with a predicted reduction in paternal age of 2.1 years (95% CI -4.9, -0.5 years). This association did not vary with maternal age, payment status, phase of study, language or ethnicity. Because previous observations are extensive, the relation of paternal age to trisomy 21 was examined further. The overall association was not significant (beta = 0.8 years; 95% CI -0.8, 2.4 years). Moreover, there was evidence that the magnitude and direction of paternal age associations vary significantly within the sample, although not between subgroups defined on the basis of payment, phase of study, language or ethnicity. With respect to maternal age, the trend is towards a greater paternal age difference for trisomy 21 losses in younger women (P = 0.058). Given the number of tests performed, the finding for trisomy 22 and reduced paternal age could be due to chance. Among trisomy types, the direction of paternal age associations was not consistent for chromosomes grouped according to characteristics that might relate to the probability of nondisjunction, such as size, arm ratio, or nucleolar organizer region content, or to the potential viability of the trisomy. Thus, neither on statistical nor biological grounds do the data provide compelling evidence of paternal age effects on the trisomies found among spontaneous abortions, or on chromosomally normal losses.

In a study of spontaneous abortions, we found an apparently robust association of trisomy with smoking that varies with maternal age. Among women under age 30, smoking either before or at the time of conception is less common in women aborting trisomic conceptions than in controls delivering at 28 weeks or later. Among older women, smoking is more common in women aborting trisomic conceptions than in controls. Our results point to an effect of smoking on the frequency of trisomic abortions that varies with age, and they suggest that the causes of recognized trisomic abortions differ in younger and older women.

The relationship between maternal age and trisomy was examined by comparing mean ages of 954 trisomic spontaneous abortions with those of live births ascertained at the same study center. The overall mean for trisomy was highly significantly elevated over that of the newborns. The age effect was most pronounced for trisomies involving the small chromosomes, with trisomies 13, 14, 15, 16, 17, 18, 20, 21, and 22 all having significantly increased ages by comparison with the control population. However, the majority of trisomies involving large or medium-sized chromosomes also had elevated mean maternal ages, suggesting that most, if not all, human trisomies are associated with increasing age of the mother. Additional variation in the age effect was observed among trisomies involving similar-sized chromosomes, indicating that factors other than chromosome size also influence the relationship between increasing age and trisomy.

Pseudomosaicism is of particular concern in prenatal diagnosis when it involves mosaicism for a cytogenetic abnormality associated with a clinical syndrome which is compatible with postnatal life, such as trisomies for chromosomes 13, 18, and 21. The lack of data regarding the outcome of pregnancies involving these specific kinds of pseudomosaicism makes genetic counselling difficult. Three cases of prenatal diagnosis of pseudomosaicism for trisomy 13, each of which had a normal outcome, will be presented (Tables 1 and 2). The three main areas for consideration are: (1) the genetic counselling issues, (2) the additional prenatal diagnostic options available to evaluate the status of the fetus in an attempt to identify some of the clinical features of trisomy 13, and (3) the outcome of the pregnancies.

In the case-control study of 118 women with autosomal trisomy identified at prenatal diagnosis and their 442 karyotypically normal matched controls, we found that there was no overall association between risk of trisomy and the presence of vaginal bleeding during pregnancy. However, a lengthy duration of bleeding appears to predict increased risk of trisomy.

The pattern of maternal age-specific incidence of autosomal trisomy in spontaneous abortions was examined for each chromosome for which a sufficient number of trisomies was observed. This included chromosomes 2, 4, 7-10, 13-16, 18, and 20-22. The rate of increase after age 30 for each of the small chromosomes (groups D-G) was similar, with the exception of chromosome 16, which showed a significantly shallower rate. The C group chromosomes tended to have an intermediate rate of increase after age 30, with the exception of chromosome 7, which had a pattern similar to the smaller chromosomes. The larger chromosomes (2 and 4) had the smallest rate of increase. There was a significant relationship between chromosome size and rate of increase after age 30 (after excluding chromosome 16), but not with rate of increase before age 30. The results suggest that autosomal trisomies may be of heterogeneous origin, with a maternal age-related factor associated with chromosome size and other sources unrelated to chromosome size. Additional evidence for and against this hypothesis is discussed.

In a consecutive series of 592 karyotyped spontaneous abortions, ten of 103 autosomal trisomies were mosaic, with a normal cell line also present. The frequency of mosaicism (10%) is much higher than that reported in Down syndrome, but similar to that reported in amniotic fluid cultures and in induced abortions. The most likely explanations for this discrepancy are (1) previous underestimation of mosaicism in live births or (2) mosaicism which is often restricted to extraembryonic fetal tissue.

The effect of maternal age on the genesis of trisomy was studied by comparing data from 362 trisomic and 790 chromosomally normal spontaneous abortions. As a group the trisomies were associated with a substantial increase in maternal age but there were considerable differences in the magnitude of the effect for different trisomies. The effect of increasing maternal age was most pronounced for trisomies involving the small chromosomes, both acrocentric and non-acrocentric. However, trisomy 16 was conspicuously different from trisomies for all the other small chromosomes, both in the reduced importance of increased maternal age and in the high frequency with which it occurred. The effect of increasing maternal age on trisomies for chromosomes in groups A, B and C was less clear than that for the small chromosomes. However, the evidence suggested that trisomy for these chromosomes was associated with a moderate increase in maternal age. It was suggested that the maternal age-dependent trisomies might result from precocious disjunction of the bivalents and random segregation of the resulting univalents, a process which would affect chromosomes with the fewest number of chiasmata and which might be more prevalent if oocytes of older women. It was further suggested that true non-disjunction, that is, the failure of bivalents to separate at anaphase, might also result in the production of trisomies. This process might be independent of, or only slightly influenced by, increasing maternal age but be affected by the presence of large blocks of heterochromatin.

It has been suggested that the maternal use of spermicidal contraceptives increases the frequency of certain congenital anomalies, including trisomy, but this issue is in dispute. This controversy led us to examine whether the use of spermicidal contraceptives is associated with an increased risk of fetal trisomy. A questionnaire concerning contraceptive use was completed by 13,729 women who were undergoing prenatal fetal chromosome studies but were as yet unaware of the results. Most women were at increased risk of having a trisomic fetus because of their advanced age. Of 154 fetuses with trisomy, 98 had trisomy 21. For each woman (case) with an affected fetus, four controls were selected from among women with chromosomally normal fetuses, matched for maternal age and medical center. Cases and controls were compared by matched-sample maximum-likelihood logistic regression, to examine the association between fetal trisomy and four measures of spermicide use: periconceptional use, timing of last use, duration of last use, and total lifetime use. No evidence was found for an association, either when all types of trisomy were combined or when trisomy 21 alone was considered. All point estimates of odds ratios relating spermicidal exposure to trisomy were approximately 1, and an effect greater than a twofold increase was excluded with 95 percent confidence in the combined-trisomy group for all measures of spermicide use.

BACKGROUND: We tested the hypothesis that trisomy risk is increased for women with fewer oocytes (older ovarian age) than other women of the same chronological age. METHODS: Our study compared three indicators of ovarian age—number of antral follicles, level of dimeric inhibin B, level of FSH—among women who had trisomic pregnancy losses (n = 54) with those among women who had other losses (24 with other chromosomally abnormal loses, 21 with chromosomally normal losses) or who had chromosomally normal births (n = 65). RESULTS: Ovarian age indicators did not differ between women with trisomic spontaneous abortions and the three comparison groups. Compared with live birth controls, adjusting for chronological age, we estimate that, on average, among trisomy cases the geometric means of 1 + follicle count, inhibin B and FSH are about 7.5% higher, 16.6% higher and 5.5% lower, respectively, with all 95% confidence intervals including zero. The sample size was sufficient to detect moderate differences (0.52 standard errors of regression) between trisomy cases and live birth controls. CONCLUSIONS: Although our data do not support our hypothesis, they leave open the possibility that changes in follicular development unrelated to the size of the oocyte pool influence abnormal chromosome segregation. [ABSTRACT FROM AUTHOR]