Showing papers on "Chromosome 21 published in 2019"

Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights.

Abstract: Down Syndrome (DS) is the most common genetic cause of intellectual disability, in which an extra copy of human chromosome 21 (HSA21) affects regional DNA methylation profiles across the genome. Although DNA methylation has been previously examined at select regulatory regions across the genome in a variety of DS tissues and cells, differentially methylated regions (DMRs) have yet to be examined in an unbiased sequencing-based approach. Here, we present the first analysis of DMRs from whole genome bisulfite sequencing (WGBS) data of human DS and matched control brain, specifically frontal cortex. While no global differences in DNA methylation were observed, we identified 3,152 DS-DMRs across the entire genome, the majority of which were hypermethylated in DS. DS-DMRs were significantly enriched at CpG islands and de-enriched at specific gene body and regulatory regions. Functionally, the hypermethylated DS-DMRs were enriched for one-carbon metabolism, membrane transport, and glutamatergic synaptic signalling, while the hypomethylated DMRs were enriched for proline isomerization, glial immune response, and apoptosis. Furthermore, in a cross-tissue comparison to previous studies of DNA methylation from diverse DS tissues and reference epigenomes, hypermethylated DS-DMRs showed a strong cross-tissue concordance, while a more tissue-specific pattern was observed for the hypomethylated DS-DMRs. Overall, this approach highlights that low-coverage WGBS of clinical samples can identify epigenetic alterations to known biological pathways, which are potentially relevant to therapeutic treatments and include metabolic pathways. These results also provide new insights into the genome-wide effects of genetic alterations on DNA methylation profiles indicative of altered neurodevelopment and brain function.

Prenatal treatment with EGCG enriched green tea extract rescues GAD67 related developmental and cognitive defects in Down syndrome mouse models

Abstract: Down syndrome is a common genetic disorder caused by trisomy of chromosome 21. Brain development in affected foetuses might be improved through prenatal treatment. One potential target is DYRK1A, a multifunctional kinase encoded by chromosome 21 that, when overexpressed, alters neuronal excitation–inhibition balance and increases GAD67 interneuron density. We used a green tea extract enriched in EGCG to inhibit DYRK1A function only during gestation of transgenic mice overexpressing Dyrk1a (mBACtgDyrk1a). Adult mice treated prenatally displayed reduced levels of inhibitory markers, restored VGAT1/VGLUT1 balance, and rescued density of GAD67 interneurons. Similar results for gabaergic and glutamatergic markers and interneuron density were obtained in Dp(16)1Yey mice, trisomic for 140 chromosome 21 orthologs; thus, prenatal EGCG exhibits efficacy in a more complex DS model. Finally, cognitive and behaviour testing showed that adult Dp(16)1Yey mice treated prenatally had improved novel object recognition memory but do not show improvement with Y maze paradigm. These findings provide empirical support for a prenatal intervention that targets specific neural circuitries.

A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21.

Abstract: Human nondisjunction errors in oocytes are the leading cause of pregnancy loss, and for pregnancies that continue to term, the leading cause of intellectual disabilities and birth defects. For the first time, we have conducted a candidate gene and genome-wide association study to identify genes associated with maternal nondisjunction of chromosome 21 as a first step to understand predisposing factors. A total of 2,186 study participants were genotyped on the HumanOmniExpressExome-8v1-2 array. These participants included 749 live birth offspring with standard trisomy 21 and 1,437 parents. Genotypes from the parents and child were then used to identify mothers with nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We performed a unique set of subgroup comparisons designed to leverage our previous work suggesting that the etiologies of meiosis I and meiosis II nondisjunction differ for trisomy 21. For the candidate gene analysis, we selected genes associated with chromosome dynamics early in meiosis and genes associated with human global recombination counts. Several candidate genes showed strong associations with maternal nondisjunction of chromosome 21, demonstrating that genetic variants associated with normal variation in meiotic processes can be risk factors for nondisjunction. The genome-wide analysis also suggested several new potentially associated loci, although follow-up studies using independent samples are required.

Gene expression dysregulation domains are not a specific feature of Down syndrome

Abstract: Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), results in a broad range of phenotypes. A recent study reported that DS cells show genome-wide transcriptional changes in which up- or down-regulated genes are clustered in gene expression dysregulation domains (GEDDs). GEDDs were also reported in fibroblasts derived from a DS mouse model duplicated for some Hsa21-orthologous genes, indicating cross-species conservation of this phenomenon. Here we investigate GEDDs using the Dp1Tyb mouse model of DS, which is duplicated for the entire Hsa21-orthologous region of mouse chromosome 16. Our statistical analysis shows that GEDDs are present both in DS cells and in Dp1Tyb mouse fibroblasts and hippocampus. However, we find that GEDDs do not depend on the DS genotype but occur whenever gene expression changes. We conclude that GEDDs are not a specific feature of DS but instead result from the clustering of co-regulated genes, a function of mammalian genome organisation.

Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR-DSCR) on human chromosome 21

Abstract: Background Down syndrome (DS) is characterized by the presence of an extra full or partial human chromosome 21 (Hsa21). An invaluable model to define genotype-phenotype correlations in DS is the study of the extremely rare cases of partial (segmental) trisomy 21 (PT21), the duplication of only a delimited region of Hsa21 associated or not to DS. A systematic retrospective reanalysis of 125 PT21 cases described up to 2015 allowed the creation of the most comprehensive PT21 map and the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. We reanalyzed at higher resolution three cases previously published and we accurately searched for any new PT21 reports in order to verify whether HR-DSCR limits could prospectively be confirmed and possibly refined. Methods Hsa21 partial duplications of three PT21 subjects were refined by adding array-based comparative genomic hybridization data. Seven newly described PT21 cases fulfilling stringent cytogenetic and clinical criteria have been incorporated into the PT21 integrated map. Results The PT21 map now integrates fine structure of Hsa21 sequence intervals of 132 subjects onto a common framework fully consistent with the presence of a duplicated HR-DSCR, on distal 21q22.13 sub-band, only in DS subjects and not in non-DS individuals. No documented exception to the HR-DSCR model was found. Conclusions The findings presented here further support the association of the HR-DSCR with the diagnosis of DS, representing an unbiased validation of the original model. Further studies are needed to identify and characterize genetic determinants presumably located in the HR-DSCR and functionally associated to the critical manifestations of DS.

SH2B3 inactivation through CN-LOH 12q is uniquely associated with B-cell precursor ALL with iAMP21 or other chromosome 21 gain.

Abstract: In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p = 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.

Male infertility: establishing sperm aneuploidy thresholds in the laboratory.

Abstract: Fluorescence in situ hybridization (FISH) in spermatozoa provides an estimate of the frequency of chromosomal abnormalities, but there is not a clinical consensus on how to statistically analyze sperm FISH results. We therefore propose a statistical approach to establish sperm aneuploidy thresholds in a fertile population. We have determined the distribution and variation of the frequency of nullisomy, disomy, and diploidy for a set of 13 chromosomes (1, 2, 9, 13, 15, 16, 17, 18, 19, 21, 22, X, and Y) in sperm nuclei from 14 fertile men by means of automatized FISH. The dispersion of data has been analyzed by the non-parametric Wilcoxon Rank Sum test. We have established the threshold values for each chromosome and aneuploidy type on the basis of the confidence interval values (99.9%). Nullisomy thresholds ranged from 0.49% for chromosome 19 to 3.09% for chromosome 22; disomy thresholds ranged from 0.30% for chromosome 21 to 1.47% for chromosome 15; diploidy thresholds ranged from 0.24% for the 9/19 chromosome set to 1.21% for the 13/21 chromosome set. Applying this approach with clinical purposes will enable us to categorize the patient as altered or normal regarding his sperm aneuploidy. Any result surpassing the cited threshold values indicates a 99.9% probability of being significantly different from fertile controls.

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome.

Abstract: Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.

Heritable variation at the chromosome 21 gene ERG is associated with acute lymphoblastic leukemia risk in children with and without Down syndrome.

Abstract: Adam J. de Smith1, Kyle M. Walsh2,3,4, Libby M. Morimoto5, Stephen S. Francis4,6, Helen M. Hansen7, Soyoung Jeon1, Semira Gonseth8, Minhui Chen1, Hanxiao Sun1, Sandra LunaFineman9, Federico Antillón10, Verónica Girón10, Alice Y. Kang5, Ivan Smirnov7, Xiaorong Shao5, Todd P. Whitehead5, Lisa F. Barcellos5, Kent W. Jolly11, Jasmine Healy12, Caroline Laverdière12, Daniel Sinnett12, Jeffrey W. Taub13, Jillian M. Birch14, Pamela D. Thompson14, Maria S. Pombo-de-Oliveira15, Logan G. Spector16, Andrew T. DeWan17, Beth A. Mueller18, Charleston Chiang1, Catherine Metayer5, Xiaomei Ma17, Joseph L. Wiemels1,4

Discovery of 33mer in chromosome 21 – the largest alpha satellite higher order repeat unit among all human somatic chromosomes

Abstract: The centromere is important for segregation of chromosomes during cell division in eukaryotes. Its destabilization results in chromosomal missegregation, aneuploidy, hallmarks of cancers and birth defects. In primate genomes centromeres contain tandem repeats of ~171 bp alpha satellite DNA, commonly organized into higher order repeats (HORs). In spite of crucial importance, satellites have been understudied because of gaps in sequencing - genomic “black holes”. Bioinformatical studies of genomic sequences open possibilities to revolutionize understanding of repetitive DNA datasets. Here, using robust (Global Repeat Map) algorithm we identified in hg38 sequence of human chromosome 21 complete ensemble of alpha satellite HORs with six long repeat units (≥20 mers), five of them novel. Novel 33mer HOR has the longest HOR unit identified so far among all somatic chromosomes and novel 23mer reverse HOR is distant far from the centromere. Also, we discovered that for hg38 assembly the 33mer sequences in chromosomes 21, 13, 14, and 22 are 100% identical but nearby gaps are present; that seems to require an additional more precise sequencing. Chromosome 21 is of significant interest for deciphering the molecular base of Down syndrome and of aneuploidies in general. Since the chromosome identifier probes are largely based on the detection of higher order alpha satellite repeats, distinctions between alpha satellite HORs in chromosomes 21 and 13 here identified might lead to a unique chromosome 21 probe in molecular cytogenetics, which would find utility in diagnostics. It is expected that its complete sequence analysis will have profound implications for understanding pathogenesis of diseases and development of new therapeutic approaches.

Combination of Genetics and Nanotechnology for Down Syndrome Modification: A Potential Hypothesis and Review of the Literature.

Abstract: Down syndrome (DS) is one of the most prevalent genetic disorders in humans. The use of new approaches in genetic engineering and nanotechnology methods in combination with natural cellular phenomenon can modify the disease in affected people. We consider two CRISPR/Cas9 systems to cut a specific region from short arm of the chromosome 21 (Chr21) and replace it with a novel designed DNA construct, containing the essential genes in chromatin remodeling for inactivating of an extra Chr21. This requires mimicking of the natural cellular pattern for inactivation of the extra X chromosome in females. By means of controlled dosage of an appropriate Nano-carrier (a surface engineered Poly D, L-lactide-co-glycolide (PLGA) for integrating the relevant construct in Trisomy21 brain cell culture media and then in DS mouse model, we would be able to evaluate the modification and the reduction of the active extra Chr21 and in turn reduce substantial adverse effects of the disease, like intellectual disabilities. The hypothesis and study seek new insights in Down syndrome modification.

Genetics and genomics of Down syndrome

Abstract: Down Syndrome (DS) is the most frequent form of intellectual disability (ID) of genetic origin, whose main features include craniofacial dysmorphisms and cardiovascular defects. In 1959, Lejeune and coll. described an extra copy of chromosome 21 (Hsa21) in children with DS (trisomy 21, or T21). We first review how different biological mechanisms may lead to the gain of genetic material of Hsa21 in the cells, originating from different combinations of genetic conditions, including a free or translocated extra copy of Hsa21, distributed in all cells or only in a part of them (mosaicism), with a complete or partial representation of the Hsa21 long arm (21q). Although it is broadly agreed that the DS phenotype originates from the altered expression of the genes located on Hsa21, its molecular pathogenesis is still unknown. We therefore illustrate how recent genomic science may be useful in the elucidation of the genotype-phenotype relationship in DS.

Mature miR-99a Upregulation in the Amniotic Fluid Samples from Female Fetus Down Syndrome Pregnancies: A Pilot Study

Abstract: Background and Objective: Although Down syndrome is the most frequent aneuploidy, its pathogenic molecular mechanisms are not yet fully understood. The aim of our study is to quantify-by qRT-PCR-the expression levels of both the mature forms and the pri-miRNAs of the microRNAs resident on chromosome 21 (miR(21)) in the amniotic fluid samples from Down syndrome singleton pregnancies and to estimate the impact of the differentially expressed microRNAs on Down syndrome fetal heart and amniocytes transcriptomes. Materials and methods: We collected amniotic fluid samples harvested by trained obstetricians as part of the second trimester screening/diagnostic procedure for aneuploidies to assess the trisomy 21 status by QF-PCR and karyotyping. Next, we evaluated-by Taqman qRT-PCR-the expression levels of both the mature forms and the pri-miRNA precursors of the microRNAs resident on chromosome 21 in amniotic fluid samples from singleton Down syndrome and euploid pregnancies. Further, we combined miRWalk 3.0 microRNA target prediction with GEO DataSets analysis to estimate the impact of hsa-miR-99a abnormal expression on Down syndrome heart and amniocytes transcriptome. Results: We found a statistically significant up-regulation of the mature form of miR-99a, but not pri-miR-99a, in the amniotic fluid samples from Down syndrome pregnancies with female fetuses. GATHER functional enrichment analysis of miRWalk3.0-predicted targets from Down syndrome amniocytes and fetal hearts transcriptome GEODataSets outlined both focal adhesion and cytokine-cytokine receptor interaction signaling as novel signaling pathways impacted by miR-99a and associated with cardiac defects in female Down syndrome patients. Conclusions: The significant overexpression of miR-99a, but not pri-miR-99a, points towards an alteration of the post-transcriptional mechanisms of hsa-miR-99a maturation and/or stability in the female trisomic milieu, with a potential impact on signaling pathways important for proper development of the heart.

A genome-wide search for new imprinted genes in the human placenta identifies DSCAM as the first imprinted gene on chromosome 21.

Abstract: We identified, through a genome-wide search for new imprinted genes in the human placenta, DSCAM (Down Syndrome Cellular Adhesion Molecule) as a paternally expressed imprinted gene. Our work revealed the presence of a Differentially Methylated Region (DMR), located within intron 1 that might regulate the imprinting in the region. This DMR showed a maternal allele methylation, compatible with its paternal expression. We showed that DSCAM is present in endothelial cells and the syncytiotrophoblast layer of the human placenta. In mouse, Dscam expression is biallelic in foetal brain and placenta excluding any possible imprinting in these tissues. This gene encodes a cellular adhesion molecule mainly known for its role in neurone development but its function in the placenta remains unclear. We report here the first imprinted gene located on human chromosome 21 with potential clinical implications.

Alterations in the Serotonin and Dopamine Pathways by Cystathionine Beta Synthase Overexpression in Murine Brain

Abstract: Cystathionine beta synthase (CBS) is one of the 225 genes on chromosome 21 (HSA 21) that are triplicated in persons with trisomy 21 (Down syndrome). Although most triplicate HSA21 genes have their orthologous genes on murine chromosome 16, the murine ortholog of hCBS is on murine chromosome 17 and thus is not present in the well-studied Ts65Dn mouse model of trisomy 21. Persons with trisomy 21 (T21) present deficits in neurotransmission and exhibit early brain aging that can partially be explained by monoamine neurotransmitter alterations. We used transgenic mice for the hCBS gene, which overexpress the CBS protein in various brain regions, to study if CBS overexpression induces modifications in the monoamine neurotransmitters in the hypothalamus, thalamus, hippocampus, and striatum from transgenic and control female and male mice aged 3–4 months and 11–12 months. Sex, age, and brain area each influenced neurotransmitter levels. Briefly, the serotonin pathway was modified by CBS overexpression in various brain areas in female mice but not in male mice. The dopamine pathway was modified in brain regions according to sex and age. These results may allow us to better understand the role of the transsulfuration pathway and especially CBS overexpression in the metabolism of biogenic amines and the catecholamine catabolism in persons with trisomy 21.

Architecture of population-differentiated polymorphisms in the human genome.

Abstract: Population variation in disease and other phenotype are partly attributed to single nucleotide polymorphisms (SNPs) in the human genome. Due to selection pressure, two individuals from the same ancestral population have more genetic similarity compared to individuals from further geographic regions. Here, we elucidated the genomic population differentiation pattern, by interrogating >22,000,000 SNPs. Majority of population-differentiated (pd) SNPs (~95%), including the potentially functional (pf) (~84%) subset reside in non-genic regions, compared to the proportion of all SNPs (58%) found in non-genic regions. This suggests that differences between populations are more likely due to differences in gene regulation rather than protein function. Actin Cytoskeleton, Axonal Guidance and Protein Kinase A signaling pathways are enriched with genes carrying at least three pdSNPs (enriched pdGenes), while Antigen Presentation, Hepatic Fibrosis and Huntington Disease Signalling pathways are over-represented by enriched pf-pdGenes. An inverse correlation between chromosome size and the proportion of pd-/pf-pdSNPs was observed. Smaller chromosomes have relatively more of such SNPs including genes carrying these SNPs. Genes associated with common diseases and enriched with these pd-/pfpdSNPs are localized to 11 different chromosomes, with immune-related disease pd/pf-pdGenes mainly residing in chromosome 6 while neurological disease pd/pf-pdGenes residing in smaller chromosomes including chromosome 21/22. The associated diseases were reported to show population differences in incidence, severity and/or etiology. In summary, this study highlights the non-sporadic nature of population differentiation footprint in the human genome, which can potentially lead to the identification of genomic regions that play roles in the manifestation of phenotypic differences, including in disease predisposition and drug response.

Sequencing Cell-Free DNA in the Maternal Circulation to Screen for Down Syndrome, Other Common Trisomies, and Selected Genetic Disorders

Abstract: Up to three-quarters of pregnant women in the USA receive prenatal screening for Down syndrome (DS) and other fetal disorders. Historically, such testing has been based on combinations of maternal age, biochemical markers, and ultrasound findings with maximal detection rate for Down syndrome of 90% (sensitivity) at a false-positive rate of 2% (1-specificity) in a general pregnancy population. In 1997, a group from Hong Kong identified “fetal” cell-free (cf)DNA in maternal circulation. Unlike serum screening, cfDNA screening for Down syndrome is based directly on detection of extra chromosome 21 material from the fetal/placental unit. Following the 2011 publication of a prospective clinical trial of cfDNA, the first commercial prenatal screening test for Down syndrome based on circulating cfDNA was introduced into clinical practice. Among over 2000 DS and 200,000 euploid samples successfully tested, the detection rate for Down syndrome by a variety of cfDNA methods is presently over 99%, with a false-positive rate of about 0.2%. Multiple methodologies introduced by different laboratories have also shown detection rates at or above 95% for both trisomy 18 and trisomy 13. Occasionally (<1% to 5%), cfDNA testing fails to provide a usable results. Many of the commercial cfDNA tests also can identify the fetal sex as well as the common sex chromosome aneuploidies. This chapter discusses the use of cfDNA for the common autosomal trisomies, sex chromosome aneuploidies, microdeletions, nonviable chromosome disorders, emerging applications, technical limitations, emerging social and ethical issues, and areas for future study.

Single cell RNA sequencing reveals cellular diversity of trisomy 21 retina

Abstract: Retina is a crucial tissue for the capturing and processing of light stimulus. Characterization of the retina at single cell level is essential for the understanding of its biological functions. A variety of abnormalities in terms of morphology and function were reported in T21 retina. To evaluate the effects of chromosome aneuploidy on retina development, we characterized single cell transcriptional profiles of a T21 fetus and performed comprehensive bioinformatic analyses. Our data revealed the diversity and heterogeneity of cellular compositions in T21 retina. In total, we identified seven major cell types, and detected several subtypes within each cell type, followed by the detection of corresponding molecular markers including previously reported ones and a series of novel markers. Our analyses identified extensive communication networks between distinct cellular types, among which a few ligand-receptor interactions were associated with the development of retina and immunoregulatory interactions. Taken together, our data provided the first single cell transcriptome profile for human T21 retina which facilitates our understanding on the dosage effects of chromosome 21 on the development of retina.

A non-mosaic humanized mouse model of Down syndrome, trisomy of a nearly complete long arm of human chromosome 21 in mouse chromosome background

Abstract: Down syndrome (DS) is a complex human condition, and animal models trisomic for human chromosome 21 (HSA21) genes or orthologs provide insights into better understanding and treating DS. However, HSA21 orthologs are distributed into three mouse chromosomes, preventing us from generating mouse models trisomy of a complete set of HSA21 orthologs. The only existing humanized mouse DS model, Tc1, carries a HSA21 with over 20% of protein coding genes (PCGs) disrupted. More importantly, due to the human centromere, Tc1 is mosaic of HSA21 (a mix of euploid and trisomic cells), which makes every mouse unique and compromises interpretation of results. Here, we used mouse artificial chromosome (MAC) technology to “clone” the 34 MB long arm of HSA21 (HSA21q). Through multiple steps of microcell-mediated chromosome transfer we created a new humanized DS mouse model, Tc(HSA21q;MAC)1Yakaz (“TcMAC21”). Constitutive EGFP expression from the transchromosome and fluorescent in situ hybridization validate that TcMAC21, containing a hybrid chromosome of HSA21q and mouse centromere, is not mosaic. Whole genome sequencing shows that TcMAC21 contains a nearly complete copy of HSA21q with 93% of intact PCGs, while RNA-seq and additional mRNA/protein expression analyses confirm that PCGs are transcribed and regulated. A battery of tests show that TcMAC21 recapitulates many DS phenotypes including morphological anomalies in heart, craniofacial skeleton and brain, pathologies at molecular and cellular level, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research. Significance Statement In the last 25 years, mouse models of trisomy 21 have supported research into Down syndrome, from defining the basis for developmental effects up to support for clinical trials. However, existing models have significant shortfalls, especially for preclinical studies. These deficiencies include incomplete or inappropriate representation of trisomic genes, absence of an extra chromosome, and mosaicism. Using cutting edge technologies we produced a mouse artificial chromosome containing the entire 34Mb long arm of human chromosome 21 and, with assisted reproductive technologies, established it in the germ line of mice. This trisomic mouse manifests developmental and functional features of Down syndrome, including hippocampal-based learning and memory deficits. This is the most complete model of Down syndrome produced to date.

Implications of intrachromosomal amplification of chromosome 21 on outcome in pediatric acute lymphoblastic leukemia: Does it affect our patients too?

Abstract: Intrachromosomal amplification (iAMP) of chromosome 21 entity is associated with a dismal outcome in B cell Acute Lymphoblastic Leukemia (B-ALL). This cytogenetic abnormality is caused by a novel mechanism; breakage-fusion-bridge cycles followed by chromothripsis along with major gross rearrangements in chromosome 21. Charts of B-ALL diagnosed at King Faisal Specialist Hospital and Research Center between 2005 and 2015 were reviewed. iAMP is a rare entity occurring at around 2.4% of all pediatrics BALL. No statistically significant difference was found among patients with iAMP21, patients with extra copies of 21 and other patients with B-ALL. The reported adverse prognostic effect of iAMP21 could be due to other coexistent adverse factors, including older age at the time of diagnosis. The most common associated abnormality in our population in addition to the hyperdiploidy was ETV6/RUNX1.