Effect of maternal age on autosomal trisomies

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 in 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.     

Parental origin of autosomal trisomies

Chromosome heteromorphisms of parents and their trisomic spontaneous abortions were compared in an attempt to determine the parental origin of 204 single trisomies, including cases of trisomy 3, 4, 9, 13, 14, 15, 16, 21 and 22, nine mosaic trisomies and nine double trisomies. Non-disjunction at maternal meiosis I was the most likely source of the additional chromosome for all trisomies studied, including the mosaics, and this was the case at all maternal ages. However, trisomy 21 had a significantly increased proportion of paternally derived cases by comparison with all other trisomies. Consideration of the sex ratio in eases of trisomy 21 of known parental origin suggests that there is an excess of males associated with paternal first meiotic division non-disjunction. The fact that this mechanism of origin is more prevalent in trisomy 21 may well explain why there is an excess of males associated with this abnormality but not with other autosomal trisomies.     

Non-disjunction of chromosome 13

We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, the largest number of cases studied to date. The parental origin was determined in every case and in 89% the extra chromosome 13 was of maternal origin with an almost equal number of maternal MI and MII errors. The latter finding is unique among human autosomal trisomies, where maternal MI (trisomies 15, 16, 21, 22) or MII (trisomy 18) errors dominate. Of the nine paternally derived cases five were of MII origin but none arose from MI errors. There was some evidence for elevated maternal age in cases with maternal meiotic origin for liveborn infants. Maternal and paternal ages were elevated in cases with paternal meiotic origin. This is in contrast to results from a similar study of non-disjunction of trisomy 21 where paternal but not maternal age was elevated. We find clear evidence for reduced recombination in both maternal MI and MII errors and the former is associated with a significant number of tetrads (33%) that are nullichiasmate, which do not appear to be a feature of normal chromosome 13 meiosis. This study supports the evidence for subtle chromosome-specific influences on the mechanisms that determine non-disjunction of human chromosomes, consistent with the diversity of findings for other trisomies.     

Investigation of maternal blood enriched for fetal cells: role in screening and diagnosis of fetal trisomies.

Prenatal diagnosis of chromosomal abnormalities relies on assessment of risk followed by invasive testing in the group with highest risk. Assessment of risk by a combination of maternal age and fetal nuchal translucency and invasive testing in the 5% of the population with the highest risk would identify about 80% of trisomy 21 pregnancies. Preliminary reports suggest that chromosomal abnormalities can also be diagnosed by fluorescent in situ hybridization (FISH) in maternal blood enriched for fetal cells. This study examines the potential role of this method on the prenatal diagnosis of fetal trisomies. Maternal blood was obtained before invasive testing in 230 pregnancies at 10-14 weeks of gestation. After enrichment for fetal cells, by triple density centrifugation and anti-CD71 magnetic cell sorting, FISH was performed and the proportion of cells with positive signals in the chromosomally normal and abnormal groups was determined. Fetal karyotype was normal in 150 cases and abnormal in 80 cases, including 36 with trisomy 21. Using a 21 chromosome-specific probe, three-signal nuclei were present in at least 5% of the enriched cells from 61% of the trisomy 21 pregnancies and in none of the normal pregnancies. For a cut-off of 3% of three-signal nuclei the sensitivity for trisomy 21 was 97% for a false positive rate of 13%. Similar values were obtained in trisomies 18 and 13 using the appropriate chromosome-specific probe. Examination of fetal cells from maternal blood may provide a noninvasive prenatal diagnostic test for trisomy 21 with the potential of identifying about 60% of affected pregnancies. Alternatively, this technique can be combined with maternal age and fetal nuchal translucency as a method of selecting the high-risk group for invasive testing. Potentially, 80% of trisomy 21 pregnancies could be identified after invasive testing in less than 1% of the pregnant population.     

Chromosomal differences in susceptibility to meiotic aneuploidy

A basic question concerning the origins of germ cell aneuploidy is whether the same mechanisms operate for all chromosomes, or whether there are chromosome-specific factors influencing the susceptibility to nondisjunction. Although selective loss of some trisomies in early gestation may contribute to the observed differences in trisomy frequency, data from spontaneous abortions, early embryos and gametes strongly suggest that there are real differences in the frequency with which different trisomies arise. In particular the preponderance of trisomy 16 and acrocentric trisomy appears to be present at conception. Maternal and paternal age relationships also differ among trisomies, as do the extent of maternal and paternal contributions, and the relative frequency of meiosis I and meiosis II errors. Recombination patterns associated with nondisjunction also show chromosomal differences. Chromosomal differences in length, centromere position, pericentromeric and other repetitive sequences, recombination patterns and chromatin characteristics might all be related to a differential susceptibility to aneuploidy, but no current explanation accounts for the excess of maternally derived trisomy 16. The existence of chromosome-specific factors makes extrapolation from observations on one chromosome to all aneuploidy unwise, both for investigations into the causes of aneuploidy, and for surveillance of aneuploidy frequency. © 1996 Wiley-Liss, Inc.     

Autosomal trisomy and maternal use of multivitamin supplements

Recent reports suggest that women carrying certain polymorphisms of folate genes associated with suboptimal folate status might be at increased risk for having a child with Down syndrome or other autosomal trisomies, and hypothesized that maternal use of multivitamin supplements might reduce such risk. To evaluate this hypothesis, we examined data from a population-based case-control study, and contrasted cases of Down syndrome, trisomy 18, and trisomy 13, with unaffected controls. Periconceptional multivitamin use, compared to no such use, was associated with an odds ratio (OR) of 0.9 (95% confidence interval [CI], 0.6-1.3) for having a pregnancy affected by an autosomal trisomy. The OR was 0.8 (95% CI, 0.5-1.3) for Down syndrome and 1.4 (95% CI, 0.5-3.6) for trisomies 13 and 18, with little variation by maternal race or age. Periconceptional multivitamin use was not associated with a major reduction in the risk for common autosomal trisomies.     

Sex ratios in fetuses and liveborn infants with autosomal aneuploidy

Ten data sources were used substantially to increase the available data for estimating fetal and livebirth sex ratios for Patau (trisomy 13), Edwards (trisomy 18), and Down (trisomy 21) syndromes and controls. The fetal sex ratio estimate was 0.88 (N = 584) for trisomy 13, 0.90 (N = 1702) for trisomy 18, and 1.16 (N = 3154) for trisomy 21. All were significantly different from prenatal controls (1.07). The estimated ratios in prenatal controls were 1.28 (N = 1409) for CVSs and 1.06 (N = 49427) for amniocenteses, indicating a clear differential selection against males, mostly during the first half of fetal development. By contrast, there were no sex ratio differences for any of the trisomies when comparing gestational ages <16 and >16 weeks. The livebirth sex ratio estimate was 0.90 (N = 293) for trisomy 13, 0.63 (N = 497) for trisomy 18, and 1.15 (N = 6424) for trisomy 21, the latter two being statistically different than controls (1.05) (N = 3660707). These ratios for trisomies 13 and 18 were also statistically different than the ratio for trisomy 21. Only in trisomy 18 did the sex ratios in fetuses and livebirths differ, indicating a prenatal selection against males >16 weeks. No effects of maternal age or race were found on these estimates for any of the fetal or livebirth trisomies. Sex ratios for translocations and mosaics were also estimated for these aneuploids. Compared to previous estimates, these results are less extreme, most likely because of larger sample sizes and less sample bias. They support the hypothesis that these trisomy sex ratios are skewed at conception, or become so during embryonic development through differential intrauterine selection. The estimate for Down syndrome livebirths is also consistent with the hypothesis that its higher sex ratio is associated with paternal nondisjunction. © 1996 Wiley-Liss, Inc.     

Investigation of maternal blood enriched for fetal cells: Role in screening and diagnosis of fetal trisomies

Prenatal diagnosis of chromosomal abnormalities relies on assessment of risk followed by invasive testing in the group with highest risk. Assessment of risk by a combination of maternal age and fetal nuchal translucency and invasive testing in the 5% of the population with the highest risk would identify about 80% of trisomy 21 pregnancies. Preliminary reports suggest that chromosomal abnormalities can also be diagnosed by fluorescent in situ hybridization (FISH) in maternal blood enriched for fetal cells. This study examines the potential role of this method on the prenatal diagnosis of fetal trisomies. Maternal blood was obtained before invasive testing in 230 pregnancies at 10–14 weeks of gestation. After enrichment for fetal cells, by triple density centrifugation and anti-CD71 magnetic cell sorting, FISH was performed and the proportion of cells with positive signals in the chromosomally normal and abnormal groups was determined. Fetal karyotype was normal in 150 cases and abnormal in 80 cases, including 36 with trisomy 21. Using a 21 chromosome-specific probe, three-signal nuclei were present in at least 5% of the enriched cells from 61% of the trisomy 21 pregnancies and in none of the normal pregnancies. For a cut-off of 3% of three-signal nuclei the sensitivity for trisomy 21 was 97% for a false positive rate of 13%. Similar values were obtained in trisomies 18 and 13 using the appropriate chromosome-specific probe. Examination of fetal cells from maternal blood may provide a noninvasive prenatal diagnostic test for trisomy 21 with the potential of identifying about 60% of affected pregnancies. Alternatively, this technique can be combined with maternal age and fetal nuchal translucency as a method of selecting the high-risk group for invasive testing. Potentially, 80% of trisomy 21 pregnancies could be identified after invasive testing in less than 1% of the pregnant population. Am. J. Med. Genet. 85:66–75, 1999. © 1999 Wiley-Liss, Inc.     

Cytological and epidemiological findings in trisomies 13, 18, and 21: England and Wales 2004-2009

This study describes the cytological and epidemiological findings in 985 trisomy 13 and 2512 trisomy 18 compared with 10,255 trisomy 21 diagnoses between 2004 and 2009 included in the National Down Syndrome Cytogenetic Register of England and Wales. The frequency of occurrence, proportions diagnosed prenatally, sex ratios, mean maternal age, and proportions of mothers with recurrences were analyzed. Ninety-seven, 98%, and 92% were free karyotypes for trisomy 21, 18, and 13, respectively; 3% of 21, 1% of 18, and 8% of trisomy 13 were translocations; and under 1% of trisomies 21 and 18 were double or triple aneuploids. Overall 1% of each trisomy had mosaicism, but 48% of the trisomy 21 double aneuploids, and 10% of trisomy 18 multiple aneuploids had mosaicism. The proportion of livebirths was 40% of trisomy 21, 11% of 18, and 13% of 13, respectively. Free trisomies 21 and 13 had an excess of males, and 18 had an excess of females, as did mosaic free trisomies 21 and 18. Mean maternal ages were 35.9 years in trisomy 21, 36.4 years in 18, and 34.6 years in 13. During the 6 years of data collection 1% of the mothers had recurrences, most recurrent trisomy 21 or 18 were identical translocations, but hetero-trisomic recurrences included 21 and 18, and 21 and 13. There are significant differences between the trisomic karyotypes and attributes, possibly related to their variable origins. Notable are the relative excess of trisomy 13 translocations, mosaicism in cases with multiple aneuploidy, and the types of homo- and hetero-recurrences.     

Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7–22.4) for trisomy 21, 5.0 (95% CI 4.8–5.1) for trisomy 18 and 2.0 (95% CI 1.9–2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9–11.5) for trisomy 21, 1.04 (95% CI 0.96–1.12) for trisomy 18 and 0.48 (95% CI 0.43–0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence.     

The origin of trisomy 13

Trisomy 13 is one of the most common trisomies in clinically recognized pregnancies and one of the few trisomies identified in liveborns, yet relatively little is known about the errors that lead to trisomy 13. Accordingly, we initiated studies to investigate the origin of the extra chromosome in 78 cases of trisomy 13. Our results indicate that the majority of cases (>91%) are maternal in origin and, similar to other autosomal trisomies, the extra chromosome is typically due to errors in meiosis I. Surprisingly, however, a large number of errors also occur during maternal meiosis II ( approximately 37%), distinguishing trisomy 13 from other acrocentric and most nonacrocentric chromosomes. As with other trisomies, failure to recombine is an important contributor to nondisjunction of chromosome 13.     

Performance of prenatal screening by non-invasive cell-free fetal DNA testing for women with various indicationsCSCD

Objective: To assess the performance of non-invasive prenatal testing (NIPT) based on massive parallel sequencing. Methods: A total of 10 275 maternal blood samples were collected. Fetal chromosomal aneuploides were subjected to low coverage whole genome sequencing. Patients with high risks received further prenatal diagnosis. The outcome of all patients were followed up. Results: High-throughput sequencing detected 72 pregnancies with fetal autosomal chromosomal aneuploidy, including 57 cases of trisomy 21, 14 cases of trisomy 18, and 1 case of trisomy 13. The positive predictive value for trisomies 21 and 18 were 98.25% and 91.67%, respectively. Comparing its performance in intermediate or high risk pregnancies, advanced maternal age pregnancies and volunteering to test pregnancies, the positive predictive value were 100%, 95%, 90% and 50%, respectively. The follow up result was only 1 case of 21 trisomy false negative with high risk. For the 56 cases of trisomy 21, the high risk group accounted for 55%, advanced maternal age accounted for 29%, the intermediate risk referred to 14%, the volunteering to test group accounted for 2%. Conclusion: The performance of NIPT for trisomies 21, 18 and 13 was satisfactory. The method can be used for women with advanced gestational age. NIPT has offered an ideal secondary screening method for those with an intermediate or high risk, and can reduce the rate of birth defects. © 2018 West China University of Medical Sciences. All rights reserved.     

Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management

Noninvasive prenatal testing by massive parallel sequencing of maternal plasma DNA has rapidly been adopted as a mainstream method for detection of fetal trisomy 21, 18 and 13. Despite the relative high accuracy of current NIPT testing, a substantial number of false-positive and false-negative test results remain. Here, we present an analysis pipeline, which addresses some of the technical as well as the biologically derived causes of error. Most importantly, it differentiates high z-scores due to fetal trisomies from those due to local maternal CNVs causing false positives. This pipeline was retrospectively validated for trisomy 18 and 21 detection on 296 samples demonstrating a sensitivity and specificity of 100%, and applied prospectively to 1350 pregnant women in the clinical diagnostic setting with a result reported in 99.9% of cases. In addition, values indicative for trisomy were observed two times for chromosome 7 and once each for chromosomes 15 and 16, and once for a segmental trisomy 18. Two of the trisomies were confirmed to be mosaic, one of which contained a uniparental disomy cell line. As placental trisomies pose a risk for low-grade fetal mosaicism as well as uniparental disomy, genome-wide noninvasive aneuploidy detection is improving prenatal management.     

A cytogenetic register of trisomies in Scotland: results of the first 2 years (1989, 1990)

A population-based register of all autosomal trisomies diagnosed in Scotland was established in 1989. Data were provided by all cytogenetic service laboratories, and included karyotype, date and place of outcome, indication for analysis, maternal age and place of residence. The Register includes all foetuses diagnosed prenatally and all cytogenetically-confirmed live- and still-births with autosomal trisomy, including partial, mosaic and familial cases. In the 2 years 1989-90, 76 prenatal and 147 postnatal diagnoses were notified. For Down syndrome karyotypes the estimated rate, assuming no terminations and after adjusting for spontaneous foetal losses following diagnosis, was 1.23 per 1000 livebirths. This was almost identical to that expected by applying published maternal age-specific rates to the maternal age distribution in Scotland, indicating a very high level of ascertainment. The adjusted rates for trisomies 13 and 18 were also close to expected values derived from published data. Prenatal screening was estimated to reduce the newborn incidence of trisomy 21 by about one quarter overall, and about one half in mothers over 35 years. For trisomy 18, the estimated overall reduction was also about one quarter. It is concluded that the Register provides a practical and cost-effective means of monitoring the effects of prenatal screening, with near-complete ascertainment. In the longer term it will provide a database for studies of the actiology of these conditions.     

Multiplex interphase FISH as a screen for common aneuploidies in spontaneous abortions

BACKGROUND: A multiplex fluorescence in-situ hybridization (FISH) strategy using chromosome-specific probes for eight chromosomes as an initial screen for chromosome abnormalities in uncultured tissues from spontaneous abortions was evaluated. METHODS: Fifty-seven prefetal spontaneous abortions were studied by karyotyping cultured cells and using FISH on uncultured cells. Two probe sets were used, identifying chromosomes 13, 15, 16, 18, 21, 22, X and Y. RESULTS: Abnormalities were detected in 53% of cases by karyotyping, and 54% of cases by FISH. FISH detected an abnormality in four of five cases where cultures failed, and in two cases where maternal cells apparently overgrew the culture. FISH missed four trisomies not identifiable with the probe sets, and one trisomy because one probe set was unscorable. FISH using these probes identified 83% of all abnormalities detected by karyotyping. CONCLUSIONS: FISH can detect abnormalities in a significant proportion of cases where the culture fails to grow or is contaminated by maternal cell growth. Multiplex FISH as an initial screen, followed by culture and karyotyping in cases where no abnormality is detected, would identify a higher proportion of chromosome abnormalities in spontaneous abortion specimens than karyotype analysis alone.     

Trisomies 13 and 18: population prevalences, characteristics, and prenatal diagnosis, metropolitan Atlanta, 1994-2003

In recent years, prenatal diagnosis and elective pregnancy termination have affected the reported birth prevalence of trisomies 13 and 18. We examined the prevalence and characteristics of these conditions using 1994-2003 data from a population-based surveillance system, the Metropolitan Atlanta Congenital Defects Program. Including fetal deaths and elective terminations increased the number of affected pregnancies by 58.7% for trisomy 13 and 72.2% for trisomy 18. Prenatal cytogenetic testing was reported in 70.8% of trisomy 13 cases and 76.1% of trisomy 18 cases. Among those with prenatal cytogenetic tests, 60.8% of trisomy 13 and 59.7% of trisomy 18 cases were electively terminated. Compared with non-Hispanic whites, non-Hispanic black race was associated with a decreased frequency of prenatal cytogenetic testing for both trisomy 13 and trisomy 18 (OR 0.24, 95% CI: 0.08-0.78 and OR 0.32, 95% CI: 0.14-0.69, respectively). The reported rates of prenatal cytogenetic testing remained stable throughout the period. As expected, maternal age > or =35 years was a risk factor for both conditions. However, while 67.1% (n = 55) of the trisomy 18 case mothers were > or =35 years, only 46.9% (n = 15) of the trisomy 13 case mothers were > or =35 years. Among live-born infants, the sex ratio among trisomy 18 infants showed an increased proportion of females: 60.4% female versus 39.6% male. However, the proportion was 48.3% female and 51.7% male among fetuses that were electively terminated in the second trimester. Inclusion of pregnancies that are prenatally diagnosed is critical for accurate surveillance and population-based analyses of these conditions.     

Tertiary trisomy due to a reciprocal translocation of chromosomes 5 and 21 in a four-generation family

Tertiary trisomy, or double trisomy, is a rare occurrence. We present two individuals with a previously unreported tertiary trisomy for chromosomes 5p and 21q in an eight-generation pedigree. Their phenotypes are compared with other partial trisomies of either 5p or 21q from the literature. The propositus was diagnosed with trisomy 21 at 2 years of age after a karyotype study for short stature and developmental delay. His phenotype was described as atypical for Down syndrome. He presented at 9 years of age because of pervasive behavioral problems and obesity. He was brachycephalic with a flattened nasal bridge, but he lacked other characteristics of trisomy 21. Because of lack of phenotypic evidence of Down syndrome, a repeat karyotype was obtained and showed 47,XY, +der(21)t(5;21)(p15.1; q22.1), incorporating partial trisomies of both chromosomes 5 and 21. Mother had a balanced translocation, 46, XX,t(5;21)(p15.1; q22.1); 8 other relatives were examined. The translocation originated from the maternal great-grandmother, but only the propositus and his mentally retarded aunt had a similar phenotye and the derivative chromosome. Fluorescence in situ hybridization showed absence of band 21q22.2 in the derivative chromosome of the propositus and his aunt, indicating that neither had trisomy for the Down syndrome critical region. These cases represent a unique double partial trisomy of chromosome arms 5p and 21q that occurred because of 3:1 malsegregation of a reciprocal translocation. These cases further demonstrate that phenotypic discordance with cytogenetic results dictate further investigation using advanced cytogenetic hybridization.     

Morphological classification of nuchal skin in human fetuses with trisomy 21, 18, and 13 at 12—18 weeks and in a trisomy 16 mouse

An increase in the nuchal translucency that can be detected at 10–14 weeks of gestation by ultrasound forms the basis for a screening test for chromosomal abnormality. Several mechanisms leading to this increase in skin thickness have been proposed, including changes of the extracellular matrix, cardiac defects and abnormalities of the large vessels. This study examines the composition of the extracellular matrix of the skin in gestational age-matched fetuses with trisomy 21, 18 and 13 from 12–18 weeks. Immunohistochemistry was applied with monoclonal and polyclonal antibodies against collagen type I, III, IV, V and VI and against laminin and fibronectin. Collagen type VI gene expression was further studied by in situ hybridization to detect differences in expression patterns of COL6A1, COL6A3 and COL1A1 between normal fetuses and those with trisomy 21. The ultrastructure of tissue samples was studied by transmission electron microscopy (TEM) and additionally by immunogold TEM. Further, we examined the morphology of the skin in an animal model for Down’s syndrome, the murine trisomy 16, by light and TEM. The dermis of trisomy 21 fetuses was richer in collagen type VI than that of normal fetuses and other trisomies, and COL6A1, located on chromosome 21, was expressed in a wider area than COL6A3, which is located on chromosome 2. Collagen type I was less abundant in the skin of trisomy 18 fetuses, while the skin of all three trisomies contained a dense network of collagen type III and V in comparison with normal fetuses. Collagen type IV, of which two genes are located on chromosome 13, was expressed in the basement membranes of the skin in all fetuses and additionally in the dermal fibroblasts only of trisomy 13 fetuses. Likewise, laminin was present in all basement membranes of normal and trisomic fetuses as well as in dermal fibroblasts of fetuses with trisomy 18. LAMA1 and LAMA3 genes are located on chromosome 18. Dermal cysts were found in the skin of trisomy 18 and 13, but not in trisomy 21 and normal fetuses. Ultrastructural findings showed that an extracellular precipitate containing glycosaminoglycans was regularly present in the skin of trisomy 21 fetuses and murine trisomy 16 embryos. In conclusion, this study suggests that the skin edema in fetal trisomies is characterized by specific alterations of the extracellular matrix that may be attributed to gene dosage effects as a result of a genetic imbalance due to the condition of fetal trisomy.     

Origin of the extra chromosome in trisomy 16

Chromosome analysis was carried out on 22 spontaneous abortuses with trisomy 16 and their parents by means of sequential Q- and C-banding techniques. In seven cases, the extra chromosome No. 16 originated from a non-disjunctional error in the first meiotic division in the mother, and in two cases from an error in the first meiotic division in the father. In two cases, non-disjunction had occurred during the second meiotic division (one in the mother and one in the father). It seems that trisomy 16, although independent of maternal age, most frequently results from a first meiotic non-disjunction in the mother.     

Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels

Although the risk of Down's syndrome increases with maternal age, women under 35 bear about 80 percent of the infants born with this condition. We prospectively investigated the utility of measuring maternal serum alpha-fetoprotein during the second trimester in women under 35 in order to identify pregnancies in which the fetus was affected with Down's syndrome. Over a two-year period, 34,354 women in this age group were screened. Amniocentesis was offered when the risk of Down's syndrome, calculated as a function of maternal age and maternal serum alpha-fetoprotein concentration adjusted for maternal weight and race, was 1:270 or higher, the risk for a 35-year-old woman. This threshold was exceeded in 1451 women in whom gestational age was confirmed by ultrasound; 9 women in this group had a fetus with the syndrome. In three women whose fetuses had trisomy 18 and one whose fetus had trisomy 13, the calculated risk of Down's syndrome was 1:270 or higher. Thus, among women in whom the risk exceeded our cutoff point, 1 in 161 were found to have a pregnancy in which the fetus was affected with Down's syndrome; the figure was 1 in 112 for all autosomal trisomies. Eighteen pregnancies involving Down's syndrome, three involving trisomy 18, and two involving trisomy 13 were not associated with a calculated risk above the cutoff point. The available data indicate that in our population, using a cutoff for risk at which 5 percent of women under 35 are offered amniocentesis, we will detect one quarter to one third of pregnancies in which the fetus has Down's syndrome.