Showing papers on "Chromosome 21 published in 2004"

Chromosome 21 and down syndrome: from genomics to pathophysiology.

Abstract: The sequence of chromosome 21 was a turning point for the understanding of Down syndrome. Comparative genomics is beginning to identify the functional components of the chromosome and that in turn will set the stage for the functional characterization of the sequences. Animal models combined with genome-wide analytical methods have proved indispensable for unravelling the mysteries of gene dosage imbalance.

Extensive gene traffic on the mammalian X chromosome.

Abstract: Mammalian sex chromosomes have undergone profound changes since evolving from ancestral autosomes. By examining retroposed genes in the human and mouse genomes, we demonstrate that, during evolution, the mammalian X chromosome has generated and recruited a disproportionately high number of functional retroposed genes, whereas the autosomes experienced lower gene turnover. Most autosomal copies originating from X-linked genes exhibited testis-biased expression. Such export is incompatible with mutational bias and is likely driven by natural selection to attain male germline function. However, the excess recruitment is consistent with a combination of both natural selection and mutational bias.

A primitive Y chromosome in papaya marks incipient sex chromosome evolution

Abstract: Many diverse systems for sex determination have evolved in plants and animals. One involves physically distinct (heteromorphic) sex chromosomes (X and Y, or Z and W) that are homozygous in one sex (usually female) and heterozygous in the other (usually male). Sex chromosome evolution is thought to involve suppression of recombination around the sex determination genes, rendering permanently heterozygous a chromosomal region that may then accumulate deleterious recessive mutations by Muller's ratchet, and fix deleterious mutations by hitchhiking as nearby favourable mutations are selected on the Y chromosome. Over time, these processes may cause the Y chromosome to degenerate and to diverge from the X chromosome over much of its length; for example, only 5% of the human Y chromosome still shows X-Y recombination. Here we show that papaya contains a primitive Y chromosome, with a male-specific region that accounts for only about 10% of the chromosome but has undergone severe recombination suppression and DNA sequence degeneration. This finding provides direct evidence for the origin of sex chromosomes from autosomes.

The DNA sequence and biology of human chromosome 19

Abstract: Chromosome 19 has the highest gene density of all human chromosomes, more than double the genome-wide average. The large clustered gene families, corresponding high G + C content, CpG islands and density of repetitive DNA indicate a chromosome rich in biological and evolutionary significance. Here we describe 55.8 million base pairs of highly accurate finished sequence representing 99.9% of the euchromatin portion of the chromosome. Manual curation of gene loci reveals 1,461 protein-coding genes and 321 pseudogenes. Among these are genes directly implicated in mendelian disorders, including familial hypercholesterolaemia and insulin-resistant diabetes. Nearly one-quarter of these genes belong to tandemly arranged families, encompassing more than 25% of the chromosome. Comparative analyses show a fascinating picture of conservation and divergence, revealing large blocks of gene orthology with rodents, scattered regions with more recent gene family expansions and deletions, and segments of coding and non-coding conservation with the distant fish species Takifugu.

The 8;21 translocation in leukemogenesis

Abstract: A common chromosomal translocation in acute myeloid leukemia (AML) involves the AML1 (acute myeloid leukemia 1, also called RUNX1, core binding factor protein (CBF alpha), and PEBP2 alpha B) gene on chromosome 21 and the ETO (eight-twenty one, also called MTG8) gene on chromosome 8 This translocation generates an AML1-ETO fusion protein t(8;21) is associated with 12% of de novo AML cases and up to 40% in the AML subtype M2 of the French-American-British classification Furthermore, it is also reported in a small portion of M0, M1, and M4 AML samples Despite numerous studies on the function of AML1-ETO, the precise mechanism by which the fusion protein is involved in leukemia development is still not fully understood In this review, we will discuss structural aspects of the fusion protein and the accumulated knowledge from in vitro analyses on AML1-ETO functions, and outline putative mechanisms of its leukemogenic potential

A chromosome 21 critical region does not cause specific Down syndrome phenotypes.

Abstract: The “Down syndrome critical region” (DSCR) is a chromosome 21 segment purported to contain genes responsible for many features of Down syndrome (DS), including craniofacial dysmorphology. We used chromosome engineering to create mice that were trisomic or monosomic for only the mouse chromosome segment orthologous to the DSCR and assessed dysmorphologies of the craniofacial skeleton that show direct parallels with DS in mice with a larger segmental trisomy. The DSCR genes were not sufficient and were largely not necessary to produce the facial phenotype. These results refute specific predictions of the prevailing hypothesis of gene action in DS.

In the platypus a meiotic chain of ten sex chromosomes shares genes with the bird Z and mammal X chromosomes

Abstract: Two centuries after the duck-billed platypus was discovered, monotreme chromosome systems remain deeply puzzling. Karyotypes of males, or of both sexes, were claimed to contain several unpaired chromosomes (including the X chromosome) that form a multi-chromosomal chain at meiosis. Such meiotic chains exist in plants and insects but are rare in vertebrates. How the platypus chromosome system works to determine sex and produce balanced gametes has been controversial for decades. Here we demonstrate that platypus have five male-specific chromosomes (Y chromosomes) and five chromosomes present in one copy in males and two copies in females (X chromosomes). These ten chromosomes form a multivalent chain at male meiosis, adopting an alternating pattern to segregate into XXXXX-bearing and YYYYY-bearing sperm. Which, if any, of these sex chromosomes bears one or more sex-determining genes remains unknown. The largest X chromosome, with homology to the human X chromosome, lies at one end of the chain, and a chromosome with homology to the bird Z chromosome lies near the other end. This suggests an evolutionary link between mammal and bird sex chromosome systems, which were previously thought to have evolved independently.

Transcript Level Alterations Reflect Gene Dosage Effects Across Multiple Tissues in a Mouse Model of Down Syndrome

Abstract: Human trisomy 21, which results in Down syndrome (DS), is one of the most complicated congenital genetic anomalies compatible with life, yet little is known about the molecular basis of DS. It is generally accepted that chromosome 21 (Chr21) transcripts are overexpressed by about 50% in cells with an extra copy of this chromosome. However, this assumption is difficult to test in humans due to limited access to tissues, and direct support for this idea is available for only a few Chr21 genes or in a limited number of tissues. The Ts65Dn mouse is widely used as a model for studies of DS because it is at dosage imbalance for the orthologs of about half of the 284 Chr21 genes. Ts65Dn mice have several features that directly parallel developmental anomalies of DS. Here we compared the expression of 136 mouse orthologs of Chr21 genes in nine tissues of the trisomic and euploid mice. Nearly all of the 77 genes which are at dosage imbalance in Ts65Dn showed increased transcript levels in the tested tissues, providing direct support for a simple model of increased transcription proportional to the gene copy number. However, several genes escaped this rule, suggesting that they may be controlled by additional tissue-specific regulatory mechanisms revealed in the trisomic situation.

DNA sequence and comparative analysis of chimpanzee chromosome 22.

Abstract: Human-chimpanzee comparative genome research is essential for narrowing down genetic changes involved in the acquisition of unique human features, such as highly developed cognitive functions, bipedalism or the use of complex language. Here, we report the high-quality DNA sequence of 33.3 megabases of chimpanzee chromosome 22. By comparing the whole sequence with the human counterpart, chromosome 21, we found that 1.44% of the chromosome consists of single-base substitutions in addition to nearly 68,000 insertions or deletions. These differences are sufficient to generate changes in most of the proteins. Indeed, 83% of the 231 coding sequences, including functionally important genes, show differences at the amino acid sequence level. Furthermore, we demonstrate different expansion of particular subfamilies of retrotransposons between the lineages, suggesting different impacts of retrotranspositions on human and chimpanzee evolution. The genomic changes after speciation and their biological consequences seem more complex than originally hypothesized.

Chromosome territory arrangement and homologous pairing in nuclei of Arabidopsis thaliana are predominantly random except for NOR-bearing chromosomes

Abstract: Differential painting of all five chromosome pairs of Arabidopsis thaliana revealed for the first time the interphase chromosome arrangement in a euploid plant. Side-by-side arrangement of heterologous chromosome territories and homologous association of chromosomes 1, 3 and 5 (on average in 35-50% of nuclei) are in accordance with the random frequency predicted by computer simulations. Only the nucleolus organizing region (NOR)-bearing chromosome 2 and 4 homologs associate more often than randomly, since NORs mostly attach to a single nucleolus. Somatic pairing of homologous approximately 100 kb segments occurs less frequently than homolog association, not significantly more often than expected at random and not simultaneously along the homologs. Thus, chromosome arrangement in Arabidopsis differs from that in Drosophila (characterized by somatic pairing of homologs), in spite of similar genome size, sequence organization and chromosome number. Nevertheless, in up to 31.5% of investigated Arabidopsis nuclei allelic sequences may share positions close enough for homologous recombination.

Gene Expression From the Aneuploid Chromosome in a Trisomy Mouse Model of Down Syndrome

Abstract: Trisomy 21 is the prototype of human aneuploidies. Since its discovery in 1959, the hypothesis has been that overexpression of the approximately 230 human chromosome 21 (Hsa21) genes result in the complex phenotype. However, the level of overexpression of Hsa21 genes in trisomic individuals is presently unknown. We have used Taqman real-time quantitative PCR to accurately measure expression of the mouse orthologs of Hsa21 in the partial trisomy mouse model Ts65Dn. The transcript levels of 78 protein-coding genes present in three copies in Ts65Dn and 21 control genes were compared between Ts65Dn and normal mouse littermates. The mean overexpression of the aneuploid genes is very close to the expected 1.5-fold in all six tissues studied. However, only approximately a third of the genes (37%) are expressed at the theoretical value of 1.5-fold. On average, 45% of the genes are expressed at significantly lower than 1.5-fold, and 9% are not significantly different from 1.0. Interestingly, 18% of the aneuploid genes were expressed at levels significantly greater than 1.5-fold. These data provide candidate genes that might be involved in the phenotypes of Down syndrome, and reveal a complex regulation of gene expression that is not only related to gene copy number.

Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes

Abstract: Molecular mechanisms of leukemogenesis have been successfully unraveled by studying genes involved in simple rearrangements including balanced translocations and inversions. In contrast, little is known about genes altered in complex karyotypic abnormalities. We studied acute myeloid leukemia (AML) patients with complex karyotypes and abnormal chromosome 21. High-resolution bacterial artificial chromosome (BAC) array-based comparative genomic hybridization disclosed amplification predominantly in the 25- to 30-megabase (MB) region that harbors the APP gene (26.3 MB) and at position 38.7-39.1 MB that harbors the transcription factors ERG and ETS2. Using oligonucleotide arrays, APP was by far the most overexpressed gene (mean fold change 19.74, P = 0.0003) compared to a control group of AML with normal cytogenetics; ERG and ETS2 also ranked among the most highly expressed chromosome 21 genes. Overexpression of APP and ETS2 correlated with genomic amplification, but high APP expression occurred even in a subset of AML patients with normal cytogenetics (10 of 64, 16%). APP encodes a glycoprotein of unknown function previously implicated in Alzheimer's disease, but not in AML. We hypothesize that APP and the transcription factors ERG and ETS2 are altered by yet unknown molecular mechanisms involved in leukemogenesis. Our results highlight the value of molecularly dissecting leukemic cells with complex karyotypes.

Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes

Abstract: Two mouse models are widely used for Down syndrome (DS) research. The Ts65Dn mouse carries a small chromosome derived primarily from mouse chromosome 16, causing dosage imbalance for approximately half of human chromosome 21 orthologs. These mice have cerebellar pathology with direct parallels to DS. The Ts1Cje mouse, containing a translocated chromosome 16, is at dosage imbalance for 67% of the genes triplicated in Ts65Dn. We quantified cerebellar volume and granule cell and Purkinje cell density in Ts1Cje. Cerebellar volume was significantly affected to the same degree in Ts1Cje and Ts65Dn, despite that Ts1Cje has fewer triplicated genes. However, dosage imbalance in Ts1Cje had little effect on granule cell and Purkinje cell density. Several mice with dosage imbalance for the segment of the Ts65Dn chromosome not triplicated in Ts1Cje had phenotypes that contrasted with those in Ts1Cje. These observations do not readily differentiate between two prevalent hypotheses for gene action in DS. Developmental Dynamics 230:581–589, 2004. © 2004 Wiley-Liss, Inc.

X-Chromosome Genetics and Human Cancer

Abstract: In mammals, the X chromosome is unique within the chromosome set. In contrast to the other chromosomes — for which two active copies are present — both male and female cells carry only one active X chromosome. This is because males have only one X chromosome and in females only one copy is active, a situation that leads to specific characteristics for genes located on this chromosome. How are the outcomes of genetic events involved in cancer — namely activation of oncogenes and inactivation of tumour suppressors — expected to be different when these genes are carried on the X chromosome rather than on autosomes?

Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome

Abstract: Down syndrome (DS) is the most common chromosomally caused form of mental retardation and is caused by trisomy of chromosome 21. The over-expression of genes located on the trisomic region has been assumed to be responsible for the phenotypic abnormalities of DS, but this hypothesis has not been confirmed fully and the very existence of gene dosage effects has been called into question. We have therefore investigated global gene expression profiles in Ts1Cje, a mouse model for DS that displays learning deficits and has a segmental trisomy of chromosome 16 orthologous to a segment of human chromosome 21 spanning from Sod1 to Znf295. DNA microarray analyses of six Ts1Cje and six normal littermate (2N) mouse brains at postnatal day 0 with probe sets representing approximately 11,300 genes revealed that the number of expressed genes and their identities in Ts1Cje mice were almost same in 2N mice. Notably, the expression levels of most genes in the trisomic region were increased approximately 1.5-fold, and the top 24 most consistently over-expressed genes in the Ts1Cje mice were all located in the trisomic region. In contrast, the expression levels of genes on other chromosomes or the euploid region of chromosome 16 were largely the same (1.0-fold) in Ts1Cje and 2N mice. These results indicate that the genes in the trisomic region of Ts1Cje are over-expressed in a dosage-dependent manner and are implicated in the molecular pathogenesis of DS.

Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21.

Abstract: Folate plays a critical role in the prevention of chromosome breakage and hypomethylation of DNA. Deficiency in this vitamin may lead to demethylation of heterochromatin causing structural centromere defects that could induce abnormal distribution of replicated chromosomes during nuclear division. Because aneuploidy of chromosomes 17 and 21 is often observed in breast cancer and leukaemia and increased risk for these cancers is associated with folate deficiency, we hypothesized that folate deficiency may lead to aneuploidy of chromosomes 17 and 21. To test these hypotheses we cultured lymphocytes from eight female volunteers (aged 40–48 years) in RPMI 1640 medium containing 12 or 120 nM of folic acid (FA) or 5-methyltetrahydrofolate (MF) for 9 days. Chromosomes 17 and 21 aneuploidies induced by folate deficiency were measured in mononucleated (MONO) and cytokinesis-blocked binucleated (BN) lymphocytes after dual-color fluorescent in situ hybridization (FISH) with a digoxigenin-labeled probe for the alphoid satellite sequence of chromosome 17 and a biotin-labeled probe for the pericentric region of chromosome 21. The results showed that 12 nm of MF or FA caused a significant 26–35% increment in frequency of aneuploidy of chromosome 17 (P = 0.0017) and aneupoidy of chromosome 21 (P = 0.0008) relative to 120 nM MF or FA. The pattern of aneuploidy in binucleated cells was significantly correlated with that observed in mononucleated cells (R = 0.51–0.75, P

Chromosome abnormalities identified in 347 spontaneous abortions collected in Japan

Abstract: Objective: We determined the incidence of specific chromosome abnormalities in this Japanese population so that comparisons could be made to the incidence of chromosome abnormalities reported for other populations. Methods: A total of 423 cases of products of conception aborted spontaneously were collected for cytogenetics analysis from various medical sites located in Japan. The cytogenetic results, along with clinical information including gestational age at the time of the miscarriage and maternal age, were compiled in a database. The incidence of specific chromosome aberrations was determined. The abnormalities were separated by gestational age at the time of the miscarriage and by maternal age. Results: The total number of specimens available for cytogenetic analysis was 407. Cytogenetic results were obtained for 347 cases (85.3%), of which 196 (56.5%) showed chromosome abnormalities. Autosomal trisomy was detected in 120 cases (61.2% of the abnormal cases). Trisomy for each autosome, with the exception of chromosomes 1, 5, 6, 11, 12, and 19, was identified. The most common autosomal trisomy was that of chromosome 16 (30 cases), followed by trisomy 21 (13 cases), and trisomy 22 (13 cases). Eight cases showed double trisomies, and one case showed trisomy for three different chromosomes. Two cases showed monosomy 21, and 24 cases showed 45,X. Triploidy was identified in 27 cases and tetraploidy was detected in five cases. Unbalanced structural rearrangements were found in 11 cases, and balanced translocations were identified in two cases. Six cases showed mosaicism: three cases showed a normal cell line; and three cases had multiple abnormal cell lines. Separating the trisomies by the gestational age at which time the miscarriage occurred revealed that trisomies 7, 8, 14, 15, 16 and 22 occurred exclusively during the first trimester and fetuses with trisomies 4, 13, 18 and 21 survived late into the second trimester. Conclusion: Overall patterns of chromosome abnormalities detected in spontaneous abortions in Japan were similar to those reported in the literature.

The complete sequence of human chromosome 5

Abstract: Chromosome 5 is one of the largest human chromosomes yet has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding and syntenic conservation with non-mammalian vertebrates, suggesting they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-encoding genes including the protocadherin and interleukin gene families and the first complete versions of each of the large chromosome 5 specific internal duplications. These duplications are very recent evolutionary events and play a likely mechanistic role, since deletions of these regions are the cause of debilitating disorders including spinal muscular atrophy (SMA).

Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and down's syndrome

Abstract: Blood gene expression profiling has been applied to a variety of hematological malignancies, autoimmune disorders, and infectious diseases. This study applies this approach to genetic diseases without obvious blood phenotypes. Three genetic diseases including tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome were compared with a group of healthy controls. RNA from whole blood was surveyed using Affymetrix U133A arrays. Each disease was associated with a unique gene expression pattern in blood that can be accurately distinguished by a classifier. Genes on chromosome 21 were overexpressed in Down's syndrome, and genes controlling cell cycle and proliferation were associated with tuberous sclerosis complex type 2 or neurofibromatosis type 1. A subset of genes involved in cardiac development or remodeling were overexpressed in patients with Down's syndrome and congenital heart defects. These findings suggest that blood gene expression profiling on a broader basis might be useful for genetic disease screening/diagnosis and might help elucidate mechanisms and pathways that lead to genotype-phenotype differences.

A detailed physical map of the horse Y chromosome

Abstract: We herein report a detailed physical map of the horse Y chromosome. The euchromatic region of the chromosome comprises ≈15 megabases (Mb) of the total 45- to 50-Mb size and lies in the distal one-third of the long arm, where the pseudoautosomal region (PAR) is located terminally. The rest of the chromosome is predominantly heterochromatic. Because of the unusual organization of the chromosome (common to all mammalian Y chromosomes), a number of approaches were used to crossvalidate the results. Analysis of the 5,000-rad horse × hamster radiation hybrid panel produced a map spanning 88 centirays with 8 genes and 15 sequence-tagged site (STS) markers. The map was verified by several fluorescence in situ hybridization approaches. Isolation of bacterial artificial chromosome (BAC) clones for the radiation hybrid-mapped markers, end sequencing of the BACs, STS development, and bidirectional chromosome walking yielded 109 markers (100 STS and 9 genes) contained in 73 BACs. STS content mapping grouped the BACs into seven physically ordered contigs (of which one is predominantly ampliconic) that were verified by metaphase-, interphase-, and fiber-fluorescence in situ hybridization and also BAC fingerprinting. The map spans almost the entire euchromatic region of the chromosome, of which 20–25% (≈4 Mb) is covered by isolated BACs. The map is presently the most informative among Y chromosome maps in domesticated species, third only to the human and mouse maps. The foundation laid through the map will be critical in obtaining complete sequence of the euchromatic region of the horse Y chromosome, with an aim to identify Y specific factors governing male infertility and phenotypic sex variation.

Molecular cytogenetic characterization of ring chromosome 15 in three unrelated patients

Abstract: We report molecular cytogenetic characterization of ring chromosome 15 in three unrelated male patients with the karyotype 46,XY,r(15). One was a stillborn child with several malformations, and the other two cases showed pre- and postnatal growth retardation and developmental delay, common features for ring chromosome 15 syndrome. One of these patients also displayed clinical features resembling Prader-Willi syndrome (PWS). To delineate the extent of the deletion on chromosome 15, we have carried out fluorescence in situ hybridization (FISH) using bacterial artificial chromosomes (BACs) mapping to the distal long arm of chromosome 15. The deletion breakpoints clustered within a 4.5-6.5 Mb region proximal to the 15q telomere. Two deletions involved the same known genes, while the largest deletion observed in the stillborn child involved three additional genes, including the COUP-TFII gene, which has been suggested to play a role in heart development. The heart malformations, which are observed in this patient, are thus likely to be due to hemizygosity/haploinsufficiency of the COUP-TFII gene. In all three patients, the insulin-like growth factor I receptor gene (IGF1R) gene was deleted supporting the association between IGF1R and growth retardation seen in ring chromosome 15 syndrome.

Genetic aspects of Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder with a complex etiology and pathogenesis. Mutations in presenilin 1 gene (PSEN1), located on chromosome 14, more rarely in amyloid-beta protein precursor (APP) on chromosome 21, and presenilin 2 genes (PSEN2) on chromosome 1, underlie the pathogenesis of most cases of familial early onset of AD (EOAD). The genetics of late-onset AD (LOAD) have been more enigmatic and the only confirmed risk factor for LOAD remains the apolipoprotein E4 allele (ApoE4) on chromosome 19. In this review, we discuss the genetics of AD with a focus on the role of the APP and presenilins.

Gene-dosage effects in Down syndrome and trisomic mouse models

Abstract: The abnormalities found in human Down syndrome (trisomy 21) have been thought to result from increased expression of genes on chromosome 21 because of their higher gene dosage. Now, several groups have shown this to be generally the case, but some inter-individual variability and other exceptions were found.

Towards an Integration of the Physical and the Genetic Chromosome Maps of Barley by in Situ Hybridization

Abstract: The relationship between physical and genetic distances on the barley chromosomes was studied by fluorescence in situ hybridization (FISH). Physical mapping of low- and single copy genes by FISH includes the protein Zx gene on chromosome 4 (4I), the α-amylase, high PI, genes on chromosome 6 (6I), the early-methionine-labelled polypeptide gene(s) on chromosome 5 (1I), and the leaf thionin genes on chromosome 6 (6I). Two interstitial sites of the telomere-associated sequence, the HvRT-family, were mapped by FISH on chromosome 3 (3I), and hybridization sites of histone 4 and ubiquitin genes were detected on chromosomes 1 (7I) and 5 (1I), respectively. In addition, a 5SrDNA locus was mapped genetically on chromosome 1. The study provides seven new anchor sites for integrating the genetic and physical chromosome maps and allows estimation of the relationship between physical and genetic distances to 1-2 Mb/cM for the distal 40 % of the chromosome arms. All chromosome arms studied showed a strongly reduced level of recombination in their inner halves. These results are discussed in relation to the feasibility of map-based cloning in barley and other cereal species.

Mitotic errors in chromosome 21 of human preimplantation embryos are associated with non-viability.

Abstract: Fluorescent in situ hybridization (FISH) studies of human preimplantation embryos have demonstrated a high proportion of chromosomal mosaicism. To investigate the different timings and nature of chromosomal mosaicism, we developed single cell multiplex fluorescent (FL)-PCR to distinguish meiotic and mitotic cell division errors. Chromosome 21 was investigated as the model chromosome as trisomy 21 (Down's syndrome) represents the most common chromosomal aneuploidy that reaches live birth. Sister blastomeres from a total of 25 chromosome 21 aneuploid embryos were analysed. Of these, 13 (52%) comprised cells with concordant DNA fingerprints indicative of meiotic non-disjunction errors. The remaining 12 (48%) aneuploid embryos comprised discordant sister blastomere allelic profiles and thus were mosaic. Errors at all stages including metaphase (MI) (12%) and first (38%), second (31%) and third (19%) mitotic cleavage divisions were identified from the types and proportion of different allelic profiles. In addition, three embryos showed combined meiotic and mitotic cell division errors including non-disjunction and anaphase lag, suggesting that diploid cells had resulted from an aneuploid zygote. However, the majority of the mosaic aneuploid embryos showed mitotic gains and losses from a diploid zygote occurring prior to the activation of the embryonic genome. Allelic profiling of amniocytes from 15 prenatal diagnosis samples displayed only meiotic errors. There appears to be a large difference between the proportion of mosaic mitotic-derived trisomy 21 embryos and fetuses. These findings indicate that mosaic mitotic error of chromosome 21 is associated with non-viability.

Identification and Molecular Characterization of a de novo Supernumerary Ring Chromosome 18 in a Patient with Klippel‐Trenaunay Syndrome

Abstract: Summary Klippel-Trenaunay syndrome (KTS) is a congenital vascular disorder comprised of capillary, venous and lymphatic malformations associated with overgrowth of the affected tissues. In this study, we report the identification of a de novo supernumerary ring chromosome in a patient with mild mental retardation, long tapering fingers, elongated, thin feet and Klippel-Trenaunay syndrome (KTS). The ring marker chromosome was found to be mosaic, present in 24% of cells, and was later shown to be derived from chromosome 18, r(18). Fluorescence in situ hybridization (FISH) was used to define the breakpoints involved in the formation of r(18). The chromosome 18p breakpoint was localized between the markers WI-9619 and D18S1150, which is less than 10 cM to the centromere. The 18q breakpoint was localized between the centromere and BAC clone 666n19, which is a region of less than 40 kb. These data suggest that the r(18) mostly originated from 18p, with an estimated size of less than 10 cM. These studies identify and characterize a new marker chromosome 18, provide insights into the understanding of the relationships between the clinical phenotypes and marker chromosomes, and establish a framework for finding a potential vascular and/or overgrowth gene located on chromosome 18.