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.     

Trisomy and triploidy are sources of embryo mortality in the zebra finch

Hatching failure is a surprisingly common phenomenon given that natural selection constantly works against it. In birds, an average of about 10 per cent of eggs across species fail to hatch, often owing to the death of embryos. While embryo mortality owing to inbreeding is both well-documented and evolutionarily plausible, this is not true for other sources of mortality. In fact, the basis for hatching failure in natural populations remains largely unexplained. Here, we demonstrate that embryo mortality in captive zebra finches (Taeniopygia guttata) follows from chromosomal aneuploidy or polyploidy. As part of microsatellite genotyping of a captive breeding population, we found 12 individuals (3.6%) with three alleles among 331 embryos that had died during development, while there were no such cases observed among 1210 adult birds. Subsequent genotyping of 1920 single nucleotide polymorphism markers distributed across the genome in birds with three alleles at microsatellite loci, and in greater than 1000 normal birds, revealed that the aberrant karyotypes involved cases of both trisomies and triploidy. Cases of both maternally and paternally inherited trisomies resulted from non-disjunction during meiosis. Maternally inherited cases of triploidy were attributable to failure of meiosis leading to diploid eggs, while paternally inherited triploidy could have arisen either from diploid sperm or from dispermy. Our initial microsatellite screening set only had the power to detect less than 10 per cent of trisomies and by extrapolation, our data therefore tentatively suggest that trisomy might be a major cause of embryo mortality in zebra finches.     

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.     

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)     

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.     

Chromosome studies in 500 induced abortions.

A survey of the chromosome constitution in 500 induced abortions (5-12 menstrual weeks) was undertaken over a period of 1 1/2 years. There were 34 cases (6.8%) of gross chromosome anomalies: 2 cases of trisomy A; 5 of trisomy C (including XXX and XXY); 1 of mosaic trisomy C; 4 of trisomy D; 2 of trisomy E; 2 of trisomy G; 1 of double trisomy E and G; 1 of XYY; 4 of monosmy C (including XO); 2 of mosaic monosomy C; 1 of mosaicism of ring D chromosome; 1 of extra small metacentric chromosome; 3 of triploidy (including triploidy with double trisomy C and G); and 5 of tetraploidy and its mosaicism. An increased risk for the occurrence of trisomic anomalies was found with advancing age of the mothers. In contrast, the production of monosomies was not age-related. Trisomies were the most common type of anomalies and were found almost at random, regardless of the characteristics of chromosomes. Neither satellited nor small chromosomes were predominantly involved in the formation of chromosome anomalies.     

Separate effects of triploidy, parentage and genomic diversity upon feeding behaviour, metabolic efficiency and net energy balance in the Pacific oyster Crassostrea gigas

Triploid oysters were induced using cytochalasin B upon retention of either the first (meiosis I triploids) or the second (meiosis II triploids) polar body in embryos from a single cohort derived from mixed parentage. Allozyme and microsatellite assays enabled the confirmation of both parentage and triploidy status in each oyster. Comparison of meiosis I triploids, meiosis II triploids and diploid siblings established that improved physiological performance in triploids was associated with increased allelic variation, rather than with the quantitative dosage effects of ploidy status. An unidentified maternal influence also interacted with genotype. Among full sibs, allelic variation measured as multi-locus enzyme heterozygosity accounted for up to 42% of the variance in physiological performance; significant positive influences were identified upon feeding rate, absorption efficiency, net energy balance and growth efficiency (= net energy balance divided by energy absorbed). Whilst allelic variation was greater in both meiosis I and meiosis II triploids than in diploid siblings, both allelic variation and net energy balance were highest in triploids induced at meiosis I. This suggests that it may be preferable to induce triploidy by blocking meiosis I, rather than meiosis II as has traditionally been undertaken during commercial breeding programmes.     

Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy,high levels of trisomy in trophoblast,and increased risk of fetal intrauterine growth restriction.

Molecular studies were performed on 101 cases of confined placental mosaicism (CPM) involving autosomal trisomy. The origin of the trisomic cell line was determined in 54 cases (from 51 pregnancies), 47 of which were also analyzed for the presence of uniparental disomy (UPD) in the disomic cell line. An additional 47 cases were analyzed for parental origin in the disomic cell line only. A somatic (postmeiotic) origin of the trisomy was observed in 22 cases and included the majority of cases with CPM for trisomy 2, 7, 8, 10, and 12. Most cases of CPM involving trisomy 9, 16, and 22 were determined to be meiotic. Fetal maternal UPD was found in 17 of 94 informative CPM cases, involving trisomy 2 (1 case), 7 (1 case), 16 (13 cases), and 22 (2 cases). The placental trisomy was of meiotic origin in all 17 cases associated with fetal UPD (P = .00005). A meiotic origin also correlated with the levels of trisomy in cultured chorionic villi samples (CVS) (P = .0002) and trophoblast (P = .00005). Abnormal pregnancy outcome (usually IUGR) correlated with meiotic origin (P = .0003), the presence of fetal UPD (P = 4 x 10(-7)), and the level of trisomy in trophoblast (P = 3 x 10(-7)) but not with the level of trisomy in CVS or term chorion. The good fit of somatic errors with the expected results could have been observed only if few true meiotic errors were misclassified by these methods as a somatic error. These data indicate that molecular determination of origin is a useful predictor of pregnancy outcome, whereas the level of trisomy observed in cultured CVS is not. In addition, UPD for some chromosomes may affect prenatal, but not postnatal, development, possibly indicating that imprinting effects for these chromosomes are confined to placental tissues.     

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)     

Identification of the origin of triploidy by HLA markers

Summary HLA-A and HLA-B markers have been determined in fibroblasts grown from tissues of triploid conceptuses and have been tested in the parents. Informative data on the origin of triploidy were obtained in eight cases: diandry I or dispermy in 4 cases, diandry II or dispermy in 2, digyny I or II in 2. This confirms that triploidy involved more frequently two sets of paternal chromosomes.     

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.     

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

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

Contribution of ultrasonographic examination to the prenatal detection of chromosomal abnormalities in 19 centres across Europe.

The objective of this study was to evaluate the prenatal detection of chromosomal abnormalities by fetal ultrasonographic examination in a large database provided by 19 Registries of Congenital Anomalies from 11 European countries. This study included 1738 cases of chromosomal abnormalities, liveborn, stillborn or termination of pregnancy regardless of maternal age from a population of 664,340 births during the period 1996 - 1998. The most frequent chromosomal anomalies were Down syndrome (n=1050), trisomy 18 (n=191), Turner syndrome (n=125), trisomy 13 (n=86), and triploidy (n=56). Fetal ultrasonographic examination resulted in the prenatal detection of 37.7% of the chromosomal abnormalities, thereby resulting in a reduction of 28.6% in their prevalence at birth due to terminations of pregnancy. The detection rate by ultrasound examination varied according to local policies of prenatal diagnosis : it was lower in countries where routine scan were not performed and higher in countries in which at least one routine anomaly scan during the second trimester of pregnancy was performed. The ultrasound detection varied according to the specific chromosomal anomaly and was lowest for Klinefelter syndrome (5.7%) and highest for triploidy (78.6%). For Down syndrome it was 26.4%. Termination of pregnancy was performed in 75.9% of the cases. Among the 655 cases detected by ultrasound, the most frequent ultrasound signs by category of chromosomal abnormalities were analysed. This study shows that ultrasound screening is an important tool in the prenatal detection of chromosomal abnormalities in Europe, leading to a significant reduction in the prevalence of livebirth children with chromosomal anomalies.     

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.     

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.     

Synthesis of glycosaminoglycans in fibroblasts from abortuses with trisomy,triploidy, and from children with Down's syndrome

Summary A comparative study has been made of glycosaminoglycan (GAG) accumulation in human fibroblasts with trisomy 7 and triploidy from spontaneous abortuses, fibroblasts with triploidy from induced abortuses, fibroblasts from patients with Down's syndrome and diploid fibroblasts from age-matched controls. The study demonstrated that the incorporation of [³H]glucosamine into hyaluronic acid by fibroblasts with trisomy 7 and triploidy, established from spontaneous abortuses, and from two out of three induced abortuses with triploidy, was 2.6–5.3 times lower than control incorporation. One strain of fibroblasts from an induced abortus with triploidy (IMG-1062) did not show any differences in GAG production when compared with diploid fibroblasts. However, the strains from children with Down's syndrome revealed normal or even increased levels of hyaluronic acid production. The data support the contention that the decreased hyaluronic acid synthesis in fibroblasts with an abnormal karyotype is related to spontaneous abortion.     

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.     

Supernumerary small marker chromosome (SMC) and uniparental disomy 22 in a child with confined placental mosaicism of trisomy 22: trisomy rescue due to marker chromosome formation

Trisomy rescue is one of various proposed mechanisms in formation of supernumerary small marker chromosomes (SMC) and uniparental disomy (UPD). In the present report a small de novo marker chromosome derived from chromosome 14 or 22 was diagnosed at prenatal diagnosis due to maternal age. Follow up investigations at birth revealed mosaicism 47,XX,+mar/46,XX. Using FISH, the marker was positive for the probe D14/22Z1, but negative for the probes midi 54 and D22Z4. Using three informative markers both chromosomes 22 were shown to be inherited from the mother (UPDmat). The results are consistent with nondisjunction at maternal meiosis I. The girl is 18 months old now and phenotypically normal. Cardiac and abdominal malformations were excluded by sonographic examinations. Motor and mental development is according to or ahead of developmental milestones (free walking with 10 months, first words at 12 months). The case confirms that maternal UPD 22 most likely is not associated with clinical abnormalities. According to FISH results, UPD 22, and 47,XX,+22 in the placenta, we conclude that the SMC was derived from alpha satellite sequences of chromosome 22. This case for the first time gives evidence that early postzygotic reduction of a chromosome to a small marker chromosome is a real existing mechanism to rescue a conceptus with trisomy.     

Genetics and biology of human ovarian teratomas. I. Cytogenetic analysis and mechanism of origin.

One hundred and two benign, mature ovarian teratomas and two immature, malignant teratomas were karyotyped and scored for centromeric heteromorphisms as part of an ongoing project to determine the chromosomal karyotype and the genetic origin of ovarian teratomas and to assess their utility for gene-centromere mapping. Karyotypic analysis of the benign cases revealed 95 46,XX teratomas and 7 chromosomally abnormal teratomas (47,XXX, 47,XX,+8 [two cases], 47,XX,+15, 48,XX,+7,+12 91,XXXX,-13 [mosaic], 47,XX,-15,+21,+mar). Our study reports on the first cases of tetraploidy and structural rearrangement in benign ovarian teratomas. The two immature cases had modal chromosome numbers of 78 and 49. Centromeric heteromorphisms that were heterozygous in the host were homozygous in 65.2% (n = 58) of the benign teratomas and heterozygous in the remaining 34.8% (n = 31). Chromosome 13 heteromorphisms were the most informative, with 72.7% heterozygosity in hosts. The cytogenetic data indicate that 65% of teratomas are derived from a single germ cell after meiosis I and failure of meiosis II (type II) or endoreduplication of a mature ovum (type III); 35% arise by failure of meiosis I (type I) or mitotic division of premeiotic germ cells (type IV).     

黄芩的花粉母细胞减数分裂及核型分析

采用压片法,对黄芩花粉母细胞减数分裂及核型进行了研究。结果表明:黄芩的大多数花粉母细胞减数分裂中染色体的行为正常,在终变期同源染色体配对后可形成9个二价体,后期Ⅰ染色体以9∶9的方式向细胞两极分离,其减数分裂为同时型;在少数花粉母细胞减数分裂中观察到落后染色体、染色体桥等异常行为;其花粉粒育性为76.49%。黄芩的染色体数目为2n=2X=18,核型公式为K(2n)=2X=18=16m+2 sm,染色体相对长度组成为2n=1 s+4M1+3M2+1L,其核型为"1A"型。