Trisomy 21 and Down syndrome

Can Down syndrome occur without trisomy 21 in the karyotype of an individual? Or vice versa can a person have trisomy 21 while unaffected by Down syndrome?

First question: No, all Down Syndrome patients have a inappropriate duplication of part or all of chromosome 21.

Second Question: More complicated. The phenotype can vary in severity depending how much much of chromosome is duplicated, whether it is duplicated and stuck onto the end of chromosome 14 (translocation vs. non-disjunction). Lastly, a rare form of this event is defined by incomplete penetrance or mosaicism of cells that contain duplication. Short Answer: No, In rare cases, a carrier can pass on trisomy 21 without being affected themselves but they themselves are a "balanced carrier" and don't have extra chromosome 21 material. See last paragraph below from the NIH and this quote from the Mayo Clinic:

When translocations are inherited, the mother or father has some rearranged genetic material, but no extra genetic material - this means he or she is a balanced carrier. A balanced carrier has no signs or symptoms of Down syndrome, but he or she can pass the translocation on to children, causing extra genetic material from chromosome 21

Types of Down Syndrome details from: NIH Down Syndrome Information Page

Research shows that three types of chromosomal changes can lead to Down syndrome.

Complete trisomy 21. In this case, an error during the formation of the egg or the sperm results in either one having an extra chromosome. So after the egg and sperm unite, the resulting cells will also have three copies of chromosome 21. The complete extra copy of chromosome 21 is in all of the person's cells-or a complete trisomy. Complete trisomy 21 is the cause of about 95% of Down syndrome cases.1,2,3

Mosaic trisomy 21. Not every cell in the body is exactly the same. In about 1% of Down syndrome cases, most of the cells in the body have the extra chromosome, but some of them don't. This is called "mosaicism." Mosaic trisomy 21 can occur when the error in cell division takes place early in development but after a normal egg and sperm unite. It can also occur early in development when some cells lose an extra chromosome 21 that was present at conception. The symptoms of someone with mosaic trisomy 21 may vary from those of someone with complete trisomy 21 or translocation trisomy 21, depending on how many cells have the extra chromosome.1,2

Translocation trisomy 21. In this type of chromosomal change, only part of an extra copy of chromosome 21 is in the cells. The extra part of the chromosome gets "stuck" to another chromosome and gets transmitted into other cells as the cells divide. This type of change causes about 4% of Down syndrome cases. There are no distinct cognitive or medical differences between people with translocation trisomy 21 and those with complete trisomy 21.

Sometimes, a parent who does not have Down syndrome may carry a translocation in chromosome 21 that can be passed on to children and cause Down syndrome. Studying the parents' chromosomes can reveal whether this is the cause of the syndrome. A genetic counsellor can assist families affected by translocation trisomy 21 in understanding the risk of Down syndrome in future pregnancies.1,2,3

Added EDIT:

Also important to note that people can have trisomy 21 develop in somatic cells spontaneously, later in life without having most of the effects of DS. But this can significantly predispose to leukemias shown here, which is an interesting area of study. Thanks to @The Nightman.

Down syndrome

Children with Down syndrome are also more likely to develop chronic respiratory infections, middle ear infections, and recurrent tonsillitis. In addition, there is a higher incidence of pneumonia in children with Down syndrome than in the general population. [2]

Children with Down syndrome have developmental delay . They are often slow to turn over, sit, and stand. Developmental delay may be related to the child's weak muscle tone. Development of speech and language may also take longer than expected. Children with Down syndrome may take longer than other children to reach their developmental milestones, but many of these milestones will eventually be met. [2]

Adults with Down syndrome have an increased risk of developing Alzheimer disease, a brain disorder that results in a gradual loss of memory, judgment, and ability to function. Although Alzheimer disease is usually a disorder that occurs in older adults, about half of adults with Down syndrome develop this condition by age 50. [2]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Trisomy 21


Trisomy 21 (Down syndrome) is the most common autosomal trisomy in newborns, and is strongly associated with increasing maternal age. Trisomy 21 results most commonly from maternal meiotic nondisjunction. Unbalanced translocation accounts for up to 4% of cases. Trisomy 21 has a distinct clinical phenotype and varying degrees of cognitive impairment. The majority of cases are detected prenatally, usually with a combination of maternal genetic screening and prenatal ultrasound. The most common structural abnormalities in trisomy 21 are increased nuchal translucency, cardiac defects, and duodenal atresia. Other possible ultrasound findings include thick nuchal fold, ventriculomegaly, absent or hypoplastic nasal bone, echogenic intracardiac focus, echogenic bowel, pyelectasis, and short limbs.

ML𠄍S: a unique clinical entity linked to TAM

Clinical features

The spectrum of acute myeloid leukaemia in Down syndrome is markedly distinct from the acute myeloid leukaemia that develops in children without Down syndrome, and the disease is now recognised as a specific entity (ML𠄍S) in the proposed World Health Organization (WHO) classification.16 ML𠄍S usually presents at between 1 and 4 years of age with a median age of presentation of 1.8 years.17 Although not all cases of ML𠄍S have a clinically evident preceding TAM phase, retrospective studies suggest that ��% of infants with TAM develop ML𠄍S either by overt progression or more commonly, after an apparent remission.18 This suggests that 𢏂𠄳% of children with Down syndrome develop ML𠄍S (given that retrospective studies suggest that �% of neonates with Down syndrome develop TAM, see above for references). However, there is a discrepancy between the incidence figures from retrospective studies and the rate of incidence of 𢏀.75% of ML𠄍S in children with Down syndrome from population�sed studies.19 This discrepancy underlines the need for prospective studies following a large cohort of neonates and children with Down syndrome.

An antecedent myelodysplastic (MDS) phase is present in 70% of infants, in which the infant becomes progressively anaemic and thrombocytopenic with dysplastic changes in erythroid cells and megakaryocytes. The marrow often becomes increasing difficult to aspirate due to hypercellularity and myelofibrosis. Delay in treatment in a well child does not compromise later outcome of chemotherapy.

Laboratory findings

The blood typically shows reduced numbers of normal cells, with dysplastic changes in all myeloid lineages, and circulating blasts. The bone marrow aspirate and trephine show dysplasia, increased blasts, abnormal megakaryocytes and variable myelofibrosis. The trephine is especially important, as aspiration of marrow is often difficult or impossible. The morphological, immunophenotypic and cytochemical profile of the blasts is similar to that of blasts seen in TAM,20,21 and in the French𠄊merican𠄋ritish (FAB) classification they are typed as AML M7 (acute megakaryoblastic leukaemia). Occasionally, other FAB types (M0, M1 and M2) are identified.22


For many years, children with Down syndrome received suboptimal treatment and had poor survival.17,23 However, following recognition of the favourable response to chemotherapy, there has been increasing recruitment to national leukaemia chemotherapy protocols. The basis of the favourable response is primarily increased sensitivity of the ML𠄍S blasts to cytarabine (reviewed by Taub and Ge24). Contemporary regimens produce 5‐year survival rates of �%.17,22,25 The main reason for treatment failure is toxicity (resistant disease and relapse are rare), predominantly due to mucositis and infection. Thus, current studies aim to reduce treatment intensity when compared with children with acute myeloid leukaemia who do not have Down syndrome.

Trisomy 21: Research breaks new ground

Down's syndrome, also known as trisomy 21, is one of the most common genetic diseases. Researchers from the University of Geneva (UNIGE) and ETH Zurich (ETHZ), Switzerland, have recently analysed the proteins of individuals with trisomy 21 for the first time: the goal was to improve our understanding of how a supernumerary copy of chromosome 21 could affect human development. Published in the journal Nature Communications, the research shows that trisomy 21, far from only affecting the proteins encoded by the chromosome 21 genes, also impacts on the proteins encoded by the genes located on the other chromosomes. In fact, the cells are overwhelmed by the protein surplus generated by the triplicated genes, and cannot regulate the amount of proteins. These results provide new insight into Down's syndrome and its symptoms based on the study of proteins, revealing the different outcomes of an excess of chromosome 21 on cell behaviour.

The symptoms of Down's syndrome -- or trisomy 21, the most common genetic disease -- include facial dysmorphism, intellectual impairment, poor muscular tone and congenital heart disease. The syndrome results from the presence of three chromosomes 21, which explains why research until now has focused on analysing DNA and transcriptome (all the messenger RNAs synthesised from genes of our genome). "Nevertheless," explains Stylianos E. Antonarakis, honorary professor in UNIGE's Faculty of Medicine, "the proteins are highly informative molecules since they are more closely linked to the clinical signs of the syndrome. Studying them makes it possible to posit new hypotheses about the cellular mechanisms disturbed by trisomy 21." However, analysing all the proteins from clinical samples is technically a very difficult task -- which is why the UNIGE researchers joined forces with a team led by Professor Ruedi Aebersold from ETHZ, who is a world expert in proteome studies.

The scientists succeeded in quantifying 4,000 out of the 10,000 proteins synthesised by skin cells -- a world premiere -- using SWATH-MS, a new mass spectrometry technique developed by ETHZ. The protein differences between the cells of Down's syndrome and a person without the genetic anomaly are low (1.5 times higher for the proteins produced by the chromosome 21 genes). They are difficult to detect with traditional techniques, meaning that it has been necessary to wait for an ultra-sensitive method to be developed in order to detect the tiny variations. "What's more, the aim was only to analyse the protein variations due to the genetic anomaly, and not the variations that can be attributed to individual differences. So, we worked on fibroblastic cells from a pair of female twins who shared the same genetic background, except that one has trisomy 21 and the other doesn't," adds Christelle Borel, a researcher in the Department of Genetics and Development at UNIGE's Faculty of Medicine.

Deficient self-regulation cellular mechanism discovered

A detailed examination of the twin's samples revealed several major findings to improve our understanding of the impact of Down's syndrome on cells. Significant quantitative variations were observed in the proteins that are not encoded exclusively from genes on chromosome 21 but that also from genes that map to other chromosomes. Trisomy 21 causes an overdose of mRNA and proteins that dysregulate the cellular functions of the affected individual. The researchers then observed a cellular mechanism for self-regulating protein production, which was capable of counteracting an unusual overabundance of proteins. Under normal conditions, this mechanism helps correct minor excesses and regulates the amount of protein needed by our cells. But, because of an extra chromosome 21, which itself encodes proteins, the cells are left with a surplus of proteins and the self-regulating mechanism is no longer able to control and restrict the quantity. "For the first time," says Professor Antonarakis, "we have a comprehensive analysis of the proteins deregulated by trisomy 21, which may explain the causes of the different symptoms of Down's syndrome."

The UNIGE geneticists also found that trisomy 21 also affected the cell's various sub-structures, especially the mitochondria, which are responsible for the cell's energy processes. But here the problem is the very opposite: the proteins that make up the mitochondria are excessively diminished and affect their correct functioning. The last result was validated with samples from other patients with trisomy 21: it showed that the type of proteins affected is also extremely important for understanding what causes the symptoms. "In general terms, protein turnover is accelerated in the trisomic cells. Then there are two kinds of proteins," says Christelle Borel. "The first assemble as a complex to perform a precise function. The second, on the other hand, operate alone. We discovered that it is the proteins in complexes that are degraded most quickly in the trisomic cells, which is something that could not have been discovered before." In fact, the proteins that assemble regulate mutually and naturally by forming the complexes, meaning their surplus is controlled. By contrast, there is an excess of solitary proteins that are not eliminated by the cell because they are functional alone.

New perspectives for research in medical genetics

The UNIGE geneticists, in collaboration with the ETHZ experts, have taken a major step forward in our understanding of trisomy 21 by going beyond the gene and transcriptome to reach proteins. These initial discoveries, together with the demonstration of the technical feasibility, open new perspectives for research, since the methodology can be applied to other genetic diseases. "We now need to find which of the deregulated proteins are responsible for each particular symptom of Down's syndrome. Then we need to see if new discoveries are possible for other types of cells such as neurons or heart cells, severely affected by trisomy 21," concludes Professor Antonarakis.

Evolutionary conservation

Model organisms will provide the basis for functional studies of the known and novel chromosome 21 genes. The genomes of Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila [25,26,27] have been completely sequenced, and thus the complete set of proteins of each of these organisms is known. Annotation of the Drosophila genome identified approximately 13,500 genes. Comparison of the translations of all annotated chromosome 21 genes with the Drosophila set identified 23 chromosome 21 gene products with similarity to a Drosophila protein over the complete length. Many of these similarities involve basic biochemical/biological functions and include such proteins as SOD1 (superoxide dismutase), GART (a purine biosynthesis enzyme), CBS (cys-tathionine beta-synthetase), and those involved in RNA splicing and the ubiquitin pathway. A further set of 31 genes showed excellent informative matches but only over a domain or subregion of the human protein. Previously known homologs include MNB (minibrain) and SIM2 (single-minded). Perhaps most interesting in both sets are those genes for which there is little or no functional data. Table 2 lists some of the known and novel chromosome 21 genes with partial and complete similarities in Drosophila. Among the novel genes, identities at the amino-acid level range as high as 64% (c21orf19) and over as many as 1,600 residues (c21orf5). Additional details remain to be resolved for example, in several cases the lengths of the human and Drosophila proteins are significantly different. Correcting these differences, if it is necessary, may strengthen the similarity data. In addition, defining complete cDNAs may reveal new homologies not discernible with partial gene models. Determining the phenotypes of mutants in the Drosophila genes is likely to shed light on the function of the homologous human genes.

Trisomy 21 and Down syndrome: a short review

Even though the molecular mechanisms underlying the Down syndrome (DS) phenotypes remain obscure, the characterization of the genes and conserved non-genic sequences of HSA21 together with large-scale gene expression studies in DS tissues are enhancing our understanding of this complex disorder. Also, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. Here we discuss the possible contribution of HSA21 genes to DS and data from global gene expression studies of trisomic samples.

Down syndrome trisomy HSA21 gene-expression analysis

Embora os mecanismos moleculares que causam a síndrome de Down (SD) não sejam totalmente conhecidos, a caracterização de genes e seqüências não gênicas conservadas do HSA21 e os estudos de expressão em grande escala em amostras de pacientes com SD estão aumentando o entendimento da síndrome. Por outro lado, os modelos murinos da SD provêm ferramentas valiosas para correlacionar genes ou segmentos cromossômicos a características fenotípicas específicas. Nesta revisão, são discutidas as possíveis contribuições dos genes do HSA21 à SD e os dados de estudos de expressão gênica global de amostras trissômicas.

Síndrome de Down trissomia do 21 HSA21 análise da expressão gênica

Trisomy 21 and Down syndrome - A short review

Trissomia do 21 e Síndrome de Down: uma breve revisão

Sommer, CA Henrique-Silva, F. * * e-mail: [email protected]

Departamento de Genética e Evolução, Universidade Federal de São Carlos – UFSCar, Rodovia Washington Luís, Km 235, CEP 13565-905, São Carlos, SP, Brazil

Even though the molecular mechanisms underlying the Down syndrome (DS) phenotypes remain obscure, the characterization of the genes and conserved non-genic sequences of HSA21 together with large-scale gene expression studies in DS tissues are enhancing our understanding of this complex disorder. Also, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. Here we discuss the possible contribution of HSA21 genes to DS and data from global gene expression studies of trisomic samples.

Keywords: Down syndrome, trisomy, HSA21, gene-expression analysis.

Embora os mecanismos moleculares que causam a síndrome de Down (SD) não sejam totalmente conhecidos, a caracterização de genes e seqüências não gênicas conservadas do HSA21 e os estudos de expressão em grande escala em amostras de pacientes com SD estão aumentando o entendimento da síndrome. Por outro lado, os modelos murinos da SD provêm ferramentas valiosas para correlacionar genes ou segmentos cromossômicos a características fenotípicas específicas. Nesta revisão, são discutidas as possíveis contribuições dos genes do HSA21 à SD e os dados de estudos de expressão gênica global de amostras trissômicas.

Palavras-chave: Síndrome de Down, trissomia do 21, HSA21, análise da expressão gênica.

Trisomy 21 is the most common genetic cause of mental retardation and one of the few aneuploidies compatible with post-natal survival. It occurs in 1 out of 700 live births in all ethnic groups (Epstein, 2001). The vast majority of meiotic errors leading to the trisomic condition occur in the egg, as nearly 90% of cases involve an additional maternal chromosome (Hassold and Sherman, 2000). Besides mental retardation, present in every individual with Down syndrome (DS), trisomy 21 is associated with more than 80 clinical traits including congenital heart disease, duodenal stenosis or atresia, imperforate anus, Hirschprung disease, muscle hypotonia, immune system deficiencies, increased risk of childhood leukemia and early onset Alzheimer's disease (Epstein et al., 1991). The severity of each of the phenotypic features is highly variable among the patients. In this sense, the identification of single nucleotide polymorphisms (SNPs) on HSA21 provides a tool to study the contribution of the allelic variability to the phenotypic variability (Deutsch et al., 2001).

It is widely assumed that the DS complex phenotype results from the dosage imbalance of the genes located on HSA21. The products of these genes act directly or indirectly, by affecting the expression of disomic genes. This hypothetical model requires different experimental approaches that include, but are not restricted to, the complete characterization of HSA21 genes and non-coding sequences and the analysis of the global gene expression changes induced by trisomy in every tissue/cell type available and at different developmental stages.

2. Human Chromosome 21

The genetic nature of DS together with the relatively small size of HSA21 encouraged scientists to concentrate efforts towards the complete characterization of this chromosome in the past few years. The almost complete DNA sequence of the long arm (21q) of HSA21 was determined and published in Nature (Hattori et al., 2000). This represented a breakthrough for research in DS, greatly assisting in the identification of every gene and non-coding sequence of 21q.

The length of 21q is 33.5 Mb and approximately 3% of its sequence encodes for proteins. The initial analysis of 21q revealed 225 genes (127 known genes and 98 putative novel genes predicted in silico) and 59 pseudogenes (Hattori et al., 2000). Although the precise gene catalogue has not yet been conclusively determined, Gardiner et al. (2003) have estimated 364 genes and putative genes from the finished sequence of HSA21. The proteins encoded by these genes fall into several functional categories including transcription factors, regulators and modulators (18 genes) proteases and protease inhibitors (6 genes) ubiquitin pathway (4 genes) interferons and immune response (9 genes) kinases (8 genes) RNA processing (5 genes) adhesion molecules (4 genes) channels (7 genes) receptors (5 genes) and energy metabolism (4 genes). Interestingly,

1% of the HSA21 corresponds to conserved non-genic (CNG) sequences, that is, sequences that are not "functionally" transcribed and do not correspond to protein-coding genes (Dermitzakis et al., 2002 Dermitzakis et al., 2004). The significant conservation of these sequences indicates that they are functional, although their function is unknown.

The identification and characterization of HSA21 genes may improve our understanding of the molecular basis of the disease. Even before the complete sequence of 21q was determined, an intensive work started towards the characterization of HSA21 genes. The existence of a "Down Syndrome Critical Region" (DSCR), a small segment of HSA21 that contains genes responsible for many features of DS, has dominated the field of DS research for three decades. Accordingly, a number of genes contained in this

5.4 Mb region have been extensively studied as an attempt to find out their potential contributions to DS. Two of these genes are DSCR1 and DSCR2.

The DSCR1 ("Down Syndrome Critical Region 1") protein, now renamed RCAN1 (from "Regulator of Calcineurin 1") (Davies et al., 2007) is over-expressed in the brain of Down syndrome fetuses and interacts physically and functionally with calcineurin A, the catalytic subunit of the Ca(2+)/calmodulin-dependent protein phosphatase PP2B (Fuentes et al., 2000 Harris et al., 2005). RCAN1 is highly expressed in the human brain and heart suggesting that its overexpression may be involved in the pathogenesis of Down syndrome, particularly mental retardation and/or cardiac defects (Fuentes et al., 1995). Previous studies identified conserved residues involved in the subcellular location of RCAN1 (Pfister et al., 2002) and provided evidence that it may play a functional role in the nucleus, probably as a regulator of transcription (Silveira et al., 2004). Recently, Arron et al. (2006) reported that the genes RCAN1 and DYRK1A, both contained within the DSCR, act synergistically to prevent the nuclear occupancy of NFATc transcription factors. They suggested that the 1.5-fold increase in dosage of RCAN1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome.

The gene DSCR2 ("Down Syndrome Critical Region 2") is highly expressed in all proliferating tissues and cells, such as fetal tissues, adult testis and cancer cell lines (Vidal-Taboada et al., 2000). The intracellular localization and proteolytic cleavage of the protein have been carefully studied (Abrão-Possik et al., 2004 Vesa et al., 2005). Hirano et al. (2005) have recently designated DSCR2 as "Proteasome Assembling Chaperone-1" (PAC1). PAC1 and PAC2 are chaperones that function as heterodimers in the maturation of mammalian 20S proteasomes. Overexpression of PAC1 or PAC2 accelerates the formation of precursor proteasomes, whereas knockdown by short interfering RNA impairs it, resulting in poor maturation of 20S proteasomes (Hirano et al., 2005). Thus, the product of the gene DSCR2 is involved in the correct assembly of 20S proteasomes.

Of note, there are eighteen genes located on HSA21 that encode transcription factors and co-regulators/modulators of transcription. These proteins are directly and indirectly involved in transcription regulation and alterations in their expression levels could impact the expression of downstream targets. This notion is supported by a number of studies reporting the dysregulation of disomic genes in DS tissues (see references below). The identification of the targets of these regulators is of prime importance to assess their contribution to the molecular pathogenesis of DS.

Despite the great efforts made in the search for a "critical region", the existence of individual loci on HSA21 responsible for producing the clinical features of DS has not been demonstrated (Shapiro, 1999). Indeed, a recent study provided the evidence that trisomy for the DSCR is necessary but not sufficient for the brain phenotypes observed in trisomic mice (Olson et al., 2007). Thus, although HSA21 genes are likely to contribute to DS, the abnormalities seen in the patients are multifactorial conditions (Shapiro, 1999) and are the result of genetic, environmental and stochastic influences (Reeves et al., 2001). Besides the complete characterization of HSA21 genes, we need to understand the transcriptional effects caused by trisomy 21.

3. Transcriptional Consequences of Trisomy 21

A model for the transcriptional consequences of trisomy has been proposed recently (FitzPatrick, 2005). An extra copy of HSA21 genes would result in a 1.5-fold increase in the expression of many of them, some of which will produce a phenotypic effect directly. Overexpression of HSA21 genes that encode trans-acting factors is expected to induce a mis-regulation of disomic genes. The primary gene-dosage effects as well as the trans-acting gene-dosage effects will produce a phenotypic effect, which will result in a tertiary apparent "mis-regulation" of disomic genes. The presence of CNG sequences on HSA21 indicates that they may also have a role in the generation of DS phenotypes although this has yet to be confirmed. Some of the genes for which evidence indicates over-expression in DS brain are listed in Table 1.

Several studies have reported a generalized overexpression of triplicated genes at the mRNA level in mouse models of DS (Amano et al., 2004 Lyle et al., 2004 Kahlem et al., 2004 Dauphinot et al., 2005). Interestingly, studies performed on human trisomic tissues indicate that only a subset of HSA21 genes is over-expressed relative to euploid controls and that the increase in expression may be different from the expected

1.5-fold (FitzPatrick et al., 2002 Tang et al., 2004 Mao et al., 2005). Also, the set of over-expressed HSA21 genes differs across the trisomic cell types (Li et al., 2006). These findings indicate that the presence of three copies of a gene does not necessarily result in overexpression and that other factors (e.g. developmental stage, tissue-specific differences) also affect gene expression.

The extensive variation in the expression of HSA21 genes observed among unaffected individuals (Deutsch et al., 2005) might underlie some of the phenotypic variability seen in the patients. The determination of which genes are significantly over-expressed in DS is largely dependent on the degree of gene-expression variation: while some HSA21 genes show little or no overlap in the distribution of expression values between DS and control samples, others show overlapping distributions with varying degrees (Prandini et al., 2007). Furthermore, a recent report indicates that many HSA21 genes are likely to be compensated in DS and some of them are highly variable among individuals (Aït Yahya-Graison et al., 2007). The genes with minimal expression overlap are over-expressed in DS and probably associated with the constant DS features those with partially overlapping expression distributions could account for the variable features. Assessment of this natural gene-expression variation in several DS tissues will provide information to identify candidate genes. In addition, the characterization of the protein profiles of trisomic samples will be of importance to see how well the transcript levels correlate with the corresponding protein products.

The increase in expression of some HSA21 genes would induce changes in the global gene expression pattern that ultimately contribute to the DS phenotypic features. A number of studies have reported dysregulation of disomic genes in DS tissues (FitzPatrick et al., 2002 Tang et al., 2004 Mao et al., 2005). Different sets of non-HSA21 genes show up- or down regulation as a consequence of chromosomal imbalance. It is likely that some (if not all) the DS phenotypic features are not directly attributable to single gene(s) but are at least in part the result of a more generalized gene dysregulation caused by the triplicated chromosome. A recent study in fetal hearts of trisomic subjects provided additional evidence supporting the existence of a dysregulation of non-HSA21 genes associated with the primary gene-dosage effect. Interestingly, functional clustering of dysregulated genes revealed down-regulation of genes encoding mitochondrial enzymes and up-regulation of genes encoding extracellular matrix proteins in DS, suggesting an association of these alterations with the heart defects (Conti et al., 2007). As each tissue is characterized by a distinct proteome, we expect that different sets of disomic genes will be subject to dysregulation in the various tissues. Therefore, every tissue/cell type available should be investigated.

We have analyzed the gene expression profile of DS lymphocytes using SAGE "Serial Analysis of Gene Expression". SAGE is a powerful technique that allows the characterization of global gene expression profiles (Velculescu et al., 1995). In the SAGE method, 10-base tags are obtained from each transcript, concatenated, and sequenced. By cataloging tags along with their frequencies and identifying corresponding genes, we can estimate the expression level of thousands of genes simultaneously. Among the significantly differentially expressed SAGE tags, many corresponded to genes involved in transcription, RNA processing, signaling, immune response and lipid metabolism. Our results suggest that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS (Sommer et al., 2008). In a previous study, we used SAGE to generate a comprehensive expression profile of DS leukocytes (Malago-Junior et al., 2005). The availability of the SAGE data may aid in the identification of gene signatures associated with specific treatments and therapeutic interventions of DS blood cells.

The studies performed on human trisomic tissues are restricted because of practical and ethical reasons. In contrast, mouse models of human disorders provide access to all tissues at all stages of development. Regardless of the species-specific differences between human and mouse, they have become indispensable tools for dissecting the phenotypic consequences of imbalances that affect single genes or chromosome segments. Although the current murine models of DS do not show all the features of the syndrome, they have greatly enhanced our understanding of the cellular and biochemical mechanisms involved.

Mouse orthologues of chromosome 21 genes are located on three chromosomes: MMU16 (

2.3 Mb). The most widely used models are the segmental trisomy strains Ts65Dn and Ts1Cje that contain several HSA21 orthologs in three copies. Both display overlapping phenotypes that parallel those seen in DS, including learning and behavioral deficits (Reeves et al., 1995 Sago et al., 1998). Two additional mouse models have been developed recently. O'Doherty et al. (2005) created the "transchromosomic" mouse Tc1, which carries an almost complete copy of HSA21 and have heart defects like those seen in DS patients, together with spatial learning and memory deficits. The segmental trisomy mouse model Ts1Rh is trisomic for the DSCR (Olson et al., 2004). Other mouse models trisomic for smaller HSA21 syntenic regions or even single genes should be generated to assess their putative contribution to the DS specific abnormalities.

5. Conclusions and Perspectives

The molecular mechanisms leading to DS are incompletely understood. The inconsistencies found in large scale transcriptome studies of trisomic tissues along with the extensive gene-expression variation of HSA21 genes indicate that more research is needed before we can elucidate the numerous pathogenic mechanisms associated with this complex disorder. In this sense, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. It will be some time before we can start considering the development of strategies for prevention and treatment of some DS related pathologies.


The most common chromosome rearrangements in humans are inversions of chromosome 9. About 2% of the world's population is heterozygous or homozygous for inversion(9). This rearrangement does not affect a person's health because the genes on the chromosome are all present - all that has changed is their relative locations. Inversion(9) is different from deletion(5) in two main respects. As mentioned above because it is a balanced rearrangement it does not cause harm. And because of this nearly everyone with an inversion(9) chromosome has inherited it from a parent who had inherited it from one of their parents and so on. In contrast, most cases of deletion(5) are due to new mutations occurring in a parent.

Symptoms of Trisomy 21

Trisomy 21 has a wide range of distinctive symptoms from external characteristics to developmental delays. Children with trisomy 21 have broad, wide faces with eyes that slant upwards. They have reduced nasal bridges, short noses and small palms with short fingers. There is usually a large gap between their big toe and second toe. Their ears are also usually small and occasionally have a small fold at the top. An enlarged tongue combined with small arched palate and small chin often leads to obstructive sleep apnea.

When these external signs are observed, a chromosomal analysis is often recommended. Further investigations are needed to understand the extent of the condition.

Many children with Trisomy 21 have congenital heart defects, intestinal malformations, and sensory impairments. Some of these infants present with fluid in the ear, or contain nerve defects that affect their ability to hear well. They are often near or far sighted, occasionally having ‘crossed eyes’. They are susceptible to thyroid malfunctions. They also have a higher probability of developing leukemia and having impaired immune functioning.

As the child grows, there are developmental delays and there is usually mild to moderate intellectual disability. These infants crawl, sit, stand and walk later than usual. Currently, there are special growth charts for children with Down’s syndrome. Their speech and language development is slower and as adults, many have vocal abnormalities with disordered speech patterns. A rapid or erratic speech rhythm often makes them unintelligible. Their ability to understand language usually exceeds their vocalization. They can have learning difficulties, either due to reduced cognitive ability or due to restricted sensory capacity.

Some people with Trisomy 21 have problems with fertility. Women with Down’s syndrome are at high risk for undergoing spontaneous abortions.

How does Trisomy 21 occur in meiosis?

Also question is, how does trisomy 21 occur during meiosis?

When nondisjunction occurs in meiosis you have a cell with 24 chromosomes and one with 22. The most common form of Down syndrome (Trisomy 21) occurs when a sperm or egg with an extra Chromosome 21 joins together with a sperm or egg with 23 chromosomes.

Subsequently, question is, does Down syndrome occur in meiosis 1 or 2? Nondisjunction occurs when homologous chromosomes (meiosis I) or sister chromatids (meiosis II) fail to separate during meiosis. The most common trisomy is that of chromosome 21, which leads to Down syndrome.

In respect to this, how does Down syndrome occur in meiosis?

During both mitosis and meiosis, there is a phase where each chromosome pair in a cell is separated, so that each new cell can get a copy of every chromosome. With Down syndrome, various types of uneven chromosome separation result in a person having an extra copy (or partial copy) of chromosome 21.

How does Nondisjunction cause Down syndrome?

TRISOMY 21 (NONDISJUNCTION) Down syndrome is usually caused by an error in cell division called &ldquonondisjunction.&rdquo Nondisjunction results in an embryo with three copies of chromosome 21 instead of the usual two. Prior to or at conception, a pair of 21st chromosomes in either the sperm or the egg fails to separate.