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PubMed1996

The frequency and mechanism of loss of heterozygosity on chromosome 11q in breast cancer.

Loss of heterozygosity (LOH, allele loss) occurs frequently on the long arm of chromosome 11 in breast cancer. Seventy-one paired tumour/normal DNA samples from breast cancer patients under 50 years old were studied for allele loss at four microsatellite loci on 11q: D11S29 (11q23.3), NCAM (11q22-q23), D11S968 (11qtel), and D11S1313 (11qcen). The maximum frequency of LOH (approximately 35 per cent) was found at the D11S29 and NCAM loci. This result is consistent with previous studies and the frequency of allele loss is moderate to high compared with the usual baseline of 0-20 per cent. In most of the cases studied, LOH on chromosome 11q could be accounted for by one of two mechanisms. Either chromosomal non-disjunction had occurred, or sequences stretching from the telomere at least as far as NCAM had undergone deletion or mitotic recombination. These results suggest that a putative tumour suppressor gene is most likely to exist near 11q22-q23. There was a very low frequency of microsatellite instability in the tumours. An association was found between lack of progesterone receptor (PgR) expression and LOH at NCAM, suggesting that deletion of sequences on 11q may prevent high levels of PgR expression in some cases.

Adult↗

PubMed1999

Monastral bipolar spindles in meiosis II of male Trichosia pubescens (Sciaridae): early stages of spindle formation and chromosome orientation.

The metaphase spindle of male meiosis II in fungus gnats (Sciaridae) is one example of naturally occurring monastral bipolar spindles. To gain further insights into how the bipolar spindle is formed in the presence of only one polar center, prometaphase of male meiosis II was investigated in the sciarid Trichosia pubescens by means of anti-tubulin immunofluorescence, DAPI chromosome staining, and electron microscopy of ultrathin serial sections. The first step in spindle formation after interkinesis seems to be the organization of an astral half-spindle, probably by MTOC activity of the astral region. With the exception of the non-disjunctional X chromosome, which always lies close to the aster, the chromosomes are found to occupy various positions with respect to the astral region, revealing different orientations of their chromatid kinetochores. It was observed that some of the mal-oriented kinetochores are associated with microtubules that, due to their orientation perpendicular to the spindle axis, are unlikely to originate from the astral region. Therefore, these mal-oriented microtubules are taken as an indication of a dispersed MTOC activity near the chromosomes or at kinetochores. According to recent models of chromosome-induced spindle self-organization [e.g., Merdes et al., 1997: J. Cell Biol. 138:953-956], they could be responsible for the formation of the other (anastral) half-spindle and for amphitelic (bipolar) orientation of the chromosomes.

Animals↗

PubMed1996

Prenatal diagnosis of Roberts syndrome: two new cases.

We report two fetuses with typical anomalies of Roberts syndrome. Prenatal diagnosis was confirmed by the characteristic disjunction of centromeres in amniocytes. We compare these cases with a child who presented with severe Roberts syndrome. We attempted to evaluate quantitatively the centromeric abnormality and the chromosome separation in the different cultures and with different methods. The variability of the clinical manifestations and cytogenetic investigations of this syndrome are reviewed.

Adult↗

PubMed1996

Confined placental mosaicism for trisomies 2, 3, 7, 8, 9, 16, and 22: their incidence, likely origins, and mechanisms for cell lineage compartmentalization.

Analysis of confined placental mosaicism (CPM) for trisomies 2, 3, 7, 8, 9, 16, and 22, in diagnostic chorionic villus sampling procedures, demonstrates apparent incidences of CPM for individual trisomies of between 9 and 91 cases per 100,000 pregnancies, with trisomy 7 being the most common. More detailed analysis of the percentage of aneuploid cells present, and the distribution of abnormality between the cytotrophoblast and extra-embryonic mesoderm cell lineages, shows a highly specific pattern for each chromosome. Theoretical considerations, in conjunction with direct observations, indicate that the overriding influence on the patterns of cell distribution seen in CPM is the distribution of aneuploid cells laid down during blastogenesis. This in turn reflects closely the origin of mosaicism from either correction of a trisomic conception or post-fertilization somatic error. The pattern of aneuploid cells for each trisomy, as seen at the end of the first trimester and later in pregnancy, can therefore be used to predict the relative contribution of meiotic and mitotic errors to CPM, and hence the likely incidences of uniparental disomy from this source, upd(16)mat being the most common (1 in 10,000 continuing pregnancies). In addition, CPM for trisomies 2, 3, and 8 shows strong evidence of a non-random distribution of aneuploid cells between the different extra-embryonic cell lineages. Analysis of comparable data from spontaneous abortion material repeats this non-random pattern for trisomies 2 and 3, and suggests that a similar phenomenon may also be occurring for trisomy 22. A non-random distribution could be attributable to selection for or against, or intolerance of, particular trisomic cells in certain lineages, but is more probably a result of either cell lineage-specific non-disjunction or consistent uneven compartmentalization of aneuploid cells during blastocyst development.

Chorionic Villi Sampling↗

PubMed1996

The sequential in utero death of heterokaryotic monozygotic twins. A case report and literature review.

A case of monozygotic twins in a 19-year-old primigravida is presented. Ultrasound examination at 15 weeks' gestation showed one twin to have a cystic hygroma and hydrops fetalis. The other twin appeared normal. The twins appeared to occupy the same amniotic cavity. Fluid was taken from the cystic hygroma under ultrasound guidance for karyotyping and this showed 45,XO chromosomes. Conservative management was adopted. Serial ultrasound examination showed deteriorating hydrops and at 26 weeks the first twin died. Intensive monitoring of the remaining twin was undertaken with weekly ultrasound, cardiotocography (CTG), and clotting screens. At 29 weeks' gestation the CTG and clotting were normal, but ultrasound revealed that multicystic encephalomalacia had developed in the second twin. A very thin dividing membrane was seen for the first time between the twins. The parents decided to terminate the pregnancy. Prior to an intracardiac potassium chloride injection, a fetal blood sample was taken which revealed 46,XX chromosomes and a normal clotting screen including natural anticoagulant levels. Labour was then induced. Delivery took place 5 h later and the woman made an uneventful recovery. The mechanism for genetic differences between monozygotic twins is discussed and the literature reviewed. A non-disjunction event around the time of splitting of the twins is proposed as the cause. The prognosis for the remaining twin is also discussed, as is the pathogenesis of the cerebral damage.

Adult↗

PubMed1996

Cytogenetic and molecular genetic characterization of trisomy 20 mosaicism in fetal blood and tissues.

We report a case of mosaic trisomy 20, the most common autosomal mosaicism identified in amniocytes, ascertained in a woman referred for amniocentesis because of abnormal ultrasound at 18.1 weeks' gestation which revealed short femurs and nuchal thickening. Metaphase analysis of 98 clones revealed 47,XY, +20 in 96 cells (98 per cent). Trisomy 20 was demonstrated in 6 cells (12 per cent) in a total of 50 cells from two fetal blood cultures obtained after pregnancy termination. Fluorescence in situ hybridization (FISH) analysis of interphase nuclei utilizing a chromosome 20 alpha-satellite centromeric DNA probe revealed three signals in 57/546 nuclei (10 per cent) in fetal blood. Metaphase analysis of 167 cells from seven different fetal tissue sources revealed trisomy 20 in 32 cells (19.2 per cent). The percentage of trisomy 20 cells varied with tissue type, with the highest percentage (13/25 cells, 52 per cent) identified in the small intestine and lymph nodes and the lowest percentage (1/34 cells, 2.9 per cent) identified in a specimen of chorionic villi. Molecular genetic analyses utilizing polymerase chain reaction (PCR)-formated dinucleotide repeat polymorphisms demonstrated that the non-disjunctional event most likely occurred post-zygotically and that the origin of the extra chromosome 20 was maternal. This study is the first to demonstrate trisomy 20 cells in fetal blood, suggesting that mosaic trisomy 20 can be embryonic in origin. In cases of prenatally detected mosaic trisomy 20, examination of fetal blood should be considered, as well as study of placental membranes, skin, and urine sediment to confirm the karyotype and determine its significance.

Adult↗

PubMed1996

Analysis of nine pregnancies with confined placental mosaicism for trisomy 2.

Karyotypically normal fetuses with completely trisomic or mosaic placentae may be at increased risk for intrauterine growth restriction (IUGR). Molecular and cytogenetic analyses on nine pregnancies with confined placental mosaicism (CPM) for trisomy 2 were performed at two collaborating centres. Seven cases were identified through prenatal testing of chorionic villi (CVS). Two of these seven cases demonstrated complete trisomy 2 while the remaining five cases showed various levels of trisomy 2 (33 per cent-75 per cent cells). Two cases identified after IUGR was observed in newborn infants demonstrated 65 per cent and 100 per cent trisomy 2 in cultured villi from term placentae. In all nine cases, blood chromosome analysis (n = 4), chromosome analysis of amniotic fluid cultures (n = 4), and cultured amnion (n = 5) were normal, failing to demonstrate any trisomic cells in tissues of fetal origin. Molecular studies on the fetal or newborn tissues using dinucleotide repeat polymorphisms on chromosome 2 revealed normal biparental inheritance of chromosome 2 in all nine cases. The parental origin studies of the extra chromosome 2 in the placenta showed that three cases were maternal in origin, at least two of which were consistent with a maternal meiotic non-disjunction giving rise to the trisomy 2, while in one case a paternal origin of the extra chromosome 2 was established.

Adult↗

PubMed1996

Prenatal diagnosis of an infant with mosaic trisomy 16 of paternal origin.

We present the first case of an infant with paternally-derived mosaic trisomy 16. Amniocentesis following an elevated maternal serum alpha-fetoprotein level and early fetal growth restriction at 19 weeks detected a high level of mosaicism with 25/33 colonies demonstrating trisomy 16 and 8/33 colonies with a normal 46,XX karyotype. Molecular studies revealed a paternal origin of the trisomy which was present in amniotic fluid cells, representing either a post-zygotic error or a meiosis II non-disjunction without crossing-over. In addition, there was normal biparental inheritance in the normal cell line. The symmetrically growth-restricted fetus was closely monitored for the remainder of the gestation. Decreased fetal movements at 36 weeks in conjunction with electronic fetal monitoring showing evidence of fetal distress necessitated abdominal delivery. Severe growth restriction, mild facial dysmorphism, and cardiac anomalies were identified. Microsatellite analysis demonstrated biparental inheritance in skin fibroblasts with a paternal origin for the trisomy in the placenta. Follow-up cytogenetic studies of additional tissues revealed 85 per cent trisomy 16 mosaicism in the placenta, yet only cytogenetically normal cells in lymphocytes and fibroblasts.

Amniocentesis↗

PubMed1998

Trisomic zygote rescue revealed by DNA polymorphism analysis in confined placental mosaicism.

Uniparental disomy can be caused by different genetic mechanisms such as gamete complementation, chromosome duplication in monosomic zygote, or post-zygotic aneuploidy correction. This last mechanism is well documented in human reproduction and is related to placental mosaicism. In the case of a trisomic zygote which has originated by paternal or maternal non-disjunction at the first or second meiotic cell division, mosaicism will result from chromosome loss and restoration of a 'normalized' diploid fetal karyotype. In order to enrich the literature with new observations on this subject, we studied by DNA polymorphism analysis ten cases of confined placental mosaicism (CPM). The finding in placental DNA of three different alleles at polymorphic loci of chromosomes 13, 16, and 20 demonstrated the trisomic status of the zygote in three cases. On the basis of these results, we believe that systematic DNA polymorphism analysis could give useful additional information to improve knowledge on aneuploidy correction in human reproduction.

Alleles↗

PubMed1999

Maternal uniparental isodisomy for chromosome 14 detected prenatally.

Maternal uniparental disomy (UPD) for chromosome 14 (upd(14)mat) has been associated with a distinct phenotype. We describe the first case of maternal uniparental isodisomy for chromosome 14 detected prenatally, in a pregnancy with mosaicism for trisomy 14 observed in both a chorionic villus sample (CVS) and in amniocytes. Detailed analysis of polymorphic microsatellites showed that the fetus was essentially isodisomic for one of the mother's chromosomes 14 and that recombination had introduced a mid-long arm region of heterodisomy. The fetus, which died in utero at 18 weeks, showed no apparent pathological features. The case demonstrates for the first time a maternal meiosis II non-disjunction of chromosome 14 leading to a trisomic conception which has been incompletely corrected by 'rescue' in the early embryo.

Adult↗

PubMed1999

Severe intra-uterine growth retardation in a patient with maternal uniparental disomy 22 and a 22-trisomic placenta.

We report on a maternal uniparental disomy of chromosome 22 in a patient with severe intra-uterine growth retardation. Karyotyping of a placental tissue revealed non-mosaic trisomy 22, whereas lymphocyte chromosomes from the newborn were normal 46,XY. Microsatellite analysis using DNA extracted from white blood cells showed maternal uniparental heterodisomy for chromosome 22. Thus, the conceptus started as maternal trisomy due to meiotic non-disjunction, and trisomy rescue occurred subsequently through loss of the paternal homologue resulting in maternal uniparental disomy. Normal phenotypes in previous reports have suggested that maternal UPD 22 has no impact on the phenotype. Thus, growth retardation in this patient was probably caused by dysfunction of the trisomic placenta.

Adult↗

PubMed1996

Centromeres of human chromosomes.

The centromere, recognized cytologically as the primary constriction, is essential for chromosomal attachment to the spindle and for proper segregation of mitotic and meiotic chromosomes. Considerable progress has been made in identifying both DNA and protein components of the centromere and kinetochore complex in mammalian chromosomes, including definition of specific motor proteins with demonstrable functions in chromosome movement. Searches for possible environmental influences on chromosome disjunction might logically be based on known components of the segregation apparatus, both intrinsic and extrinsic to the chromosomes themselves. This article reviews available information on both DNA and protein components of the centromere of mammalian, particularly human, chromosomes and summarizes our current understanding of their role(s) in facilitating normal chromosome behavior in mitosis and meiosis.

Animals↗

PubMed1996

Parental age-related aneuploidy in human germ cells and offspring: a story of past and present.

Parental age is the most important aetiological factor in trisomy formation in humans. Cytogenetic studies on germ cells reviewed here imply that (i) 2-4% sperm are aneuploid and 8.6% oocytes from IVF are hyperploid (ii) a paternal age effect may exist, and (iii) oocytes of aged women contain precociously separated chromatids in metaphase II. Trisomy data suggest that most aneuploidy is generated during meiosis I of oogenesis and is maternal age-dependent. Trisomy 18 is unique, originating mostly from maternal meiosis II errors. The extra gonosome in 47, XXY derives mostly from a paternal meiosis I error. Trisomy of individual chromosomes may remain low, linearly rise, or exponentially increase with advanced maternal age. Maternal age related trisomies involve achiasmatic and normochiasmate chromosomes, and chromosomes with disturbed recombination and distally located chiasmata. Hypotheses on the origin of the maternal age effect are critically reviewed. One model is presented that relates to altered cell cycle and protein phosphorylation in oocytes of aged mammals and accounts for most of the observed data in humans and in experimental studies. Aneuploidy may thus involve a predetermined component but is possibly also influenced by extrinsic factors reducing oocyte quality or depleting the oocyte pool precociously. Areas of future research are proposed to elucidate (i) the significance of early disturbances in the prenatal ovary, (ii) parameters diminishing the quality of oocytes in dictyate stage, and (iii) mechanisms enabling oocytes to process all chromosomal configurations successfully during later stages of oogenesis. Studies with newly developed and existing animal models appear indispensable to identify exposures affecting chromosome disjunction during meiosis, especially in the aging female.

Age Factors↗

PubMed2000

Trisomy 12 mosaicism confirmed in multiple organs from a liveborn child.

This patient, in whom trisomy 12 mosaicism was confirmed in multiple organs, is the fifth case diagnosed postnatally and the first reported for whom a meiotic origin of the trisomy, maternal meiosis I, was determined. Mosaic aneuploidy was suspected because of pigmentary dysplasia, a frequent but non-specific finding in chromosomal mosaicism. The severe phenotype of this child, who died in infancy with a complex heart malformation, was probably a result of the high percentage of trisomic cells. Cytogenetic and interphase fluorescent in situ hybridization analyses showed a highly variable distribution of aneuploid cells in the nine tissues studied, from none in blood and ovary to 100% in spleen and liver. The trisomy arose meiotically with apparent post-zygotic loss of one of the chromosomes 12; uniparental disomy for this chromosome in the diploid cell line was excluded. The phenotype of the cases reported in living or liveborn individuals has been extremely variable, ranging from the present case, in which the child died in infancy with multiple malformations and pigmentary dysplasia, to a fortuitous finding in an adult studied for infertility. The variation in severity is probably determined by the proportion and distribution of the trisomic cells, which is linked to the timing of the non-disjunctional error.

Abnormalities, Multiple↗

PubMed2001

Recurrent trisomy 15 in a female carrier of der(15)t(Y;15)(q12;p13).

We report on a female carrier of der(15) t(Y;15)(q12;p13) who had two pregnancy losses with trisomy 15 and one with tetraploidy. Molecular analysis showed that both non-disjunction events resulting in the trisomy 15 pregnancies occurred in maternal meiosis I. This finding raises the possibility that there may be an increased risk for trisomy 15 in some carriers of unbalanced t(Y;15) which, if followed by trisomic zygote rescue, may lead to uniparental disomy (UPD).

Abortion, Habitual↗

PubMed2000

Prenatal diagnosis and genetic analysis of X chromosome polysomy 49, XXXXY.

We report on the prenatal diagnosis, genetic analysis and clinical manifestations of a 49,XXXXY fetus. A 31-year-old, primigravida woman was referred for genetic counselling at 17 weeks' gestation with the sonographic findings of intrauterine growth retardation, generalized oedema, a large septated cystic hygroma colli measuring 5x4 cm, and abnormal posturing of the lower extremities. Quantitative fluorescent polymerase chain reaction (QF-PCR) with small tandem repeat (STR) markers specific for chromosome X and a pentanucleotide marker X22 for the Xq/Yq pseudoautosomal region PAR2 rapidly detected the X-chromosome polysomy from amniotic fluid cells. This abnormality appeared to arise from successive non-disjunction during maternal meiosis I and meiosis II. Cytogenetic analysis revealed a karyotype of 49,XXXXY. Our case shows that a 49,XXXXY fetus in the second trimester may demonstrate hydrops fetalis and a large septated cystic hygroma colli by prenatal ultrasound. Our case also shows that QF-PCR assays with sex chromosome specific STR markers provide rapid prenatal diagnosis of numerical sex chromosome aneuploidy as well as its genetic cause in fetal cystic hygroma.

Abnormalities, Multiple↗

PubMed1977

Schizophrenic cognitive dysfunction: a deficit in rule transfer.

This study examined conceptual rule learning (RL) deficit in male schizophrenic Ss categorized into three groups as defined by Whitaker Index of Schizophrenic Thinking (WIST). Ss were administered a conjunctive, disjunctive, conditional or biconditional rule learning task, WIST, and Shipley-Hartford Memory Scale. It was shown that: (a) the WIST reliably differentiates among three levels of thought disorder as reflected by a deficit in inter-problem transfer of rule learning; (b) certain WIST and Shipley parameters reliably predict RL performance; and (c) phenothiazine dosage levels show no influence on the WIST and no correlation with RL. The findings indicate that cognitive dysfunction in schizophrenics is evidenced by limited inductive reasoning, insufficient channel capacity for filtering out irrelevant information, and inability to gain from antecedent RL experience. Principal locus of schizophrenic thought disorder is examined within a stimulus encoding-information processing paradigm.

Adult↗

PubMed2000

Multiple copies of mutant BRCA1 and BRCA2 alleles in breast tumors from germ-line mutation carriers.

Inactivation of the BRCA1 and BRCA2 breast cancer susceptibility genes has been reported to occur via a germ-line mutation of one allele and a somatic loss of the remaining wild-type allele. We investigated the genetic mechanisms behind the second event in breast tumors from 17 BRCA1 and eight BRCA2 germ-line mutation carriers, as compared with 21 sporadic breast tumors. Microsatellite markers intragenic or in close proximity to both genes were used to analyze imbalances between the mutant and wild-type alleles. The actual and relative gene copy numbers were scored by fluorescence in situ hybridization (FISH) analysis of tumor cells using locus and centromere specific probes. All but one of the informative BRCA1 and BRCA2 tumors exhibited allelic imbalance and loss of the corresponding wild type allele. In contrast to sporadic tumors, however, where allelic imbalance at the BRCA1 and BRCA2 loci correlated well with relative copy number losses by FISH, a simple reduction to a single copy (average copy number ratio 2:1) was found in only two BRCA1 (12%) and four BRCA2 (50%) tumors. The majority of BRCA1 and BRCA2 tumors showed a copy number reduction (relative to reference probe with ratios 4:2, 3:2, 4:3) at corresponding loci, suggesting that a specific physical deletion of the wild-type BRCA gene allele has been followed by a duplication of the remaining mutant allele via polyploidization. Several tumors contained multiple copies of BRCA1 and BRCA2 genes without relative copy number changes, implying that loss of wild-type alleles is executed by alternative mechanisms such as mitotic recombination, non-disjunctional chromosomal loss with or without reduplication, or by gene conversion. A paradoxical relative copy number gain of the mutant allele was evident in three BRCA1 tumors (18%), which could be of biological relevance if a dominant negative or gain-of-function model was ascribed for certain BRCA1 mutants. Our results indicate that complex genetic alterations are operational at the BRCA1 and BRCA2 loci in tumors from genetically predisposed individuals.

Alleles↗