Down syndrome (DS), or trisomy 21 (Ts21), is the most common genetic developmental disorder with a prevalence of about one in 700 live births. The triplication of human chromosome 21 (Hsa21) that characterizes this disorder results in a constellation of cognitive and physical alterations. The cognitive deficits range from mild to severe, and persist throughout life. Post-mortem studies of individuals with DS have revealed various neuropathologic abnormalities that are thought to underlie cognitive dysfunction, including: disruption of neurogenesis, corticogenesis, synapse formation, and myelination. However, the etiology of these alterations remains largely unknown. In order to elucidate the genetic basis of DS-phenotypes, several mouse models have been developed. The Ts65Dn, Ts1Cje, and Ts16 models, recapitulate DS-related phenotypes and have extended our knowledge of the associated pathological changes. Despite this progress, genetic dissimilarities in mouse models may confound phenotypic comparisons between mouse models and human DS. Specifically, the aforementioned models have a limited subset of triplicated Hsa-21 homologs or contain non-syntenic genes. Recently, a novel mouse model, the Dp(16)1Yey/+ (or Dp16), that has the entire Hsa-21 syntenic region of Mmu16 triplicated and no non-syntenic genes has been developed, suggesting that Dp16 may present phenotypes more closely matching the human disorder. In this study, we present the first comprehensive analysis of Dp16 embryonic, young and adult brains that includes a focus on the proliferative, inhibitory/excitatory neuronal and oligodendrocyte-lineage phenotypes using histological, immunohistochemical, and behavioral assessments. We hypothesize that due to the larger triplicated segment, the Dp16 mouse model better recapitulates DS-related neuropathologies relative to other mouse models. Despite the extended triplication, Dp16 animals lack DS-related embryonic phenotypes, however, behavioral and cellular phenotypes arise during the 2nd week following birth. The Dp16 is the first model of DS to develop postnatal phenotypes in the absence of changes to embryonic brain development, as such, Dp16 may not be a reliable model to further understand brain development in the DS fetus. However, when used in conjuncture with other models, the Dp16 will be a useful tool in understanding the contribution of aneuploidy and gene dosage to DS-phenotypes in mouse models of DS.

No description available.

Down syndrome, also referred to as trisomy 21, is a chromosomal abnormality in which the 21st human chromosome is partially or entirely duplicated. It is associated with a myriad of characteristics, including distinct facial deformities, intellectual disability, a heart defect, low muscle tone, and development of Alzheimer's disease symptoms with aging. This duplication is associated with increased levels of gene expression relative to what is present in euploid cells and disrupts the structure of some gene products. This study examines current mouse models of trisomy 21, describes a bioinformatics approach to evaluate relationships between genes on chromosome 21, and to determine the role they may play in Down syndrome associated intellectual disability. The Ts1Rhr, Tc1, and Ts65Dn mouse models are compared and contrasted to human trisomy 21. Representation of intellectual disability is determined by how the mice in each model perform on learning and memory tasks. Each model is examined for duplication of Down syndrome associated genes as well as for body weight, cerebral size, cerebellar size, balance, motor coordination, learning and memory, attention, activity, presence or absence of a heart defect, and presence or absence of a craniofacial defect. Next, a bioinformatics approach is proposed as tool with the capacity to examine the individual genes on chromosome 21, the relationships between the genes, group genes together by functional similarity and biological implication, and then establish which of these groups are enriched. The combined evaluation of mouse models and bioinformatics can be used as an innovative way to study the involvement in the intellectual disability associated with Down syndrome. Through the review of current mouse models and the evaluation of individual chromosome 21 genes using bioinformatics resources, the study seeks to determine what insights on intellectually disability can be gained.

Trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13) represent the most common autosomal trisomies detected in live-born infants. Previous studies have addressed interventions, morbidities and survival in term or near-term infants with T21, T18 or T13, or were limited by a small number of patients. However, the combination of one of these chromosomal anomalies and very low birth weight (VLBW) presents greater challenges. Data from the NICHD Neonatal Research Network (NRN) and from the Vermont Oxford Network (VON) databases were used to examine the frequency, interventions, risk of mortality and neonatal morbidities, including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD), among VLBW infants with T21, T18 or T13 compared to VLBW infants without major birth defects (BD) and VLBW infants with non-chromosomal BD. Anthropometric VON charts for the assessment of birth weight for gestational age among 22 week to term infants with T21, T18 or T13 were also developed. In the VON database (n=539,509), the frequency of VLBW infants diagnosed with T21 was 1681 (0.31%), with T18 was 1416 (0.27%), and with T13 was 435 (0.08%). Major surgery was reported for 30.4% of infants with T21, 9.2% with T18, and 6.8% with T13. In-hospital mortality occurred for 33.1% of infants with T21, 89.0% with T18, and 92.4% with T13. Median survival time was 4 days (95% CI: 3-4) among infants with T18 and 3 days (95% CI: 2-4) among infants with T13. Birth weight for gestational age charts were created using VON data with a total of 5147 infants with T21 aged 22-41 weeks, 1053 infants with T18 aged 22-41 weeks, and 613 infants with T13 aged 22-40 weeks. Among the three groups, infants with T18 were the most likely to be growth restricted while infants with T21 were the least likely to be growth restricted. The new anthropometric VON charts for infants with T21 were also compared to the Lubchenco and Fenton charts and both showed frequent misclassification of infants with T21 as small or large for gestational age. In the NICHD NRN database (n=52,259), 133 (0.26%) VLBW infants were diagnosed with T21, 132 (0.25%) with T18 and 40 (0.08%) with T13. The adjusted relative risk, estimated using Poisson regression models with robust variance estimators, showed an increased risk of death, PDA, NEC, LOS, and BPD among infants with T21 relative to infants with no BD. Relative to infants with non-chromosomal BD, infants with T21 were at increased risk of PDA and NEC. A trend toward a lower risk of ROP was observed among infants with T21 compared to infants with non-chromosomal BD and infants without major BD. Infants with T13, but not infants with T18, were less likely to be mechanically ventilated than infants with T21 and infants without BD. Infants with T18 had increased risk of PDA compared to infants with T13, infants with T21 and infants without BD and increased risk of BPD compared to infants with T21 and infants without BD. The current studies evaluated the largest cohorts of VLBW infants with T21, T18 or T13. These data are important to help families and care providers make informed decisions involving the care of their VLBW infants with these chromosomal anomalies.

Childhood acute leukemias are genetically complex disorders, with recurrent or random aberrations found in most patients. Their proper functional characterization is crucial for understanding the role they play in the process of leukemogenesis. We aimed to identify and characterize the genetic background of two leukemic entities. The transient myeloproliferative disorder (TMD) is a preleukemic condition that occurs in 10% of newborns with Down syndrome. Trisomy 21 together with in-utero gained mutations in the GATA1 gene are essential in TMD and represent an ideal "multi-hit" model to study leukemogenesis. We investigated an alternative pathogenic mechanism enabling TMD development in a confirmed absence of trisomy 21. Novel deletions in the GATA1 and JAK1 genes were described as potential drivers of this TMD. The deletion D65_C228 in GATA1 results in the expression of an aberrant isoform, which is predicted to lose transactivation potential and, more importantly, to partially lose the ability of recognizing physiological DNA binding sites, possibly triggering TMD alone. Our thorough characterization of JAK1 F636del questions its role in TMD development. Analysis of JAK/STAT signaling suggested decrease of kinase activity upon F636 loss. Cells harboring the aberrant JAK1 did not obtain cytokine-...

Maintenance of gene dosage is important for proper cellular function and development, as evidenced by the natural silencing of one X-chromosome in mammalian females, and by the embryonic lethality of most autosomal aneuploidy. A notable exception is Down syndrome (DS), which occurs in 1/700 newborns. It has been known for 50+ years that DS is caused by trisomy for chromosome 21 (chr21), yet biological understanding remains wanting; even what cell types and pathways are impacted by chr21 dosage has remained unclear. Given the complexity of DS, better experimental approaches have been needed. This thesis advances understanding of DS pathobiology using an innovative approach that translates the X-inactivation mechanism via the XIST gene, to an inducible system to “silence trisomy” in DS patient-derived iPSCs and their differentiated derivatives. I investigated the most immediate and direct effects of silencing trisomy on mRNAs genome-wide. Initial studies revealed trisomy 21 (T21) impairs early developmental pathways for two major cell type processes: neurogenesis and, surprisingly, angiogenesis. Further analysis of endothelial cells showed chr21 overexpression reduces pathways relating to cell migration, projection, and signaling, and functional assays showed delayed response to angiogenic cues causing a deficit in microvessel formation. The previously unknown cell-autonomous effect of T21 on angiogenesis has broad significance for systems impacted, including brain and heart development, and comorbidities throughout life such as early-onset Alzheimer’s disease. This work also has implications for understanding of dosage sensitivity and genome balance, a fundamental but poorly understood aspect of genome biology.

Bakgrund: Down Syndrom (DS) är den kromosomavvikelsen som är vanligast i Sverige. Kännetecken ses vid födseln. Barn med DS löper stor risk att få somatiska problem. Screening används för att undersöka kromosomavvikelser hos fostret och kan skapa etiska dilemman mellan vårdpersonal och föräldrar. Sjuksköterskan arbetssätt var holistiskt, det hjälper föräldrarna att få en fungerande framtid.  Syfte: Syftet med denna studie var att beskriva föräldrars erfarenheter av att leva med barn som har Down Syndrom. Metod: En beskrivande litteraturstudie, där de bibliografiska databaserna PubMed och Cinahl användes för att hitta artiklar. 11 artiklar inkluderades i litteraturstudien. Fem teman identifierades: (1) Ändrade livssituationer utifrån barnens specifika omsorgsbehov, (2) Föräldrars utveckling och påverkan, (3) Känslor gällande barnets framtid, (4) Social acceptans, (5) Kontakt med hälso- och sjukvården. Huvudresultat: Resultatet påvisade föräldrarnas ändrade livssituationer utifrån barnet med DS omsorgsbehov. Utmaningarna föräldrar ställdes inför visade en personlig utveckling och påverkan på livssituationen. Resultatet visade en oro inför barnets framtid och vuxenliv. Föräldrarnas erfarenheter av social acceptans gentemot barn med DS var varierande likväl erfarenheterna av kontakten med hälso-och sjukvården utifrån barnets diagnos. Slutsats: Liknande oroskänslor kring framtiden för barnen med DS är genomgående i studierna. Problemet är bristen på kunskap och forskning i sjukvården gällande diagnosen DS och påverkan på familjen. Bristfällig information och stöd ökade föräldrarnas stress. Det krävs fortsatt forskning kring ämnet DS och hur en sjuksköterska ska bemöta föräldrar vid olika möten. Genom god kunskap inom ämnet kan en sjuksköterska hjälpa familjer att leva sitt liv så normalt som möjligt / Background: Down syndrome (DS) is the most common chromosome disorder in Sweden. Characteristics is seen at birth. Children with DS have increased risk to develop somatic problems. Screening is used to examine chromosomal abnormalities in the fetus and this can cause ethical dilemmas between healthcare personnel and parents. Nurses work with a holistically approach, it helps parents to have a functional future. Purpose:  The purpose of this study was to describe parents' lived experience of living with a child that has the diagnosis Down syndrome. Method: A descriptive literature review with a thematic design. The bibliographic databases PubMed and Cinahl were used to find articles. 11 articles were included in the study. Five themes were identified: (1) Changed life situations on the child's specific need of care, (2) Parents’ growth and impact, (3) Emotions regarding the child's future, (4) Social acceptance, (5) Contact with healthcare services. Main result: The studies show that parents have had to change their life situations due to the child's caring need. The challenges that parents are faced with showed a personal growth and affected them on a personal level. The result showed a concern for the children's future and adulthood. Parents experiences regarding social acceptance and the contact with healthcare against children with DS was varied. Conclusion: Similar concerns regarding the future for the children with DS is consistently seen all through the studies. The problem is the lack of knowledge and research within the healthcare system regarding DS and the effects it has on the family. Lackluster information and support. Inadequate information and support increased the parents stress levels. Further research regarding DS and how the nurse should treat parents in encounters with them is important. A nurse can through good knowledge help families live their lives as normal as possible.

Indiana University-Purdue University Indianapolis (IUPUI) / Down syndrome (DS) is a genetic disorder that results from triplication of human chromosome 21 (Hsa21) and occurs in around 1 in 1000 live births. All individuals with DS present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences between males and females with DS suggest a sexual dimorphism in how trisomy affects skeletal deficits associated with trisomy 21 (Ts21). Previous investigations of skeletal abnormalities in DS have varied methodology, sample sizes and ages making the underlying causes of deficits uncertain. Mouse models of DS were used to characterize skeletal abnormalities, but the genetic and developmental origin remain unidentified. Over-expression Dyrk1a, found on Hsa21 and mouse chromosome 16 (Mmu16) has been linked to cognitive deficits and skeletal deficiencies. Dp1Tyb mice contain three copies of all of the genes on Mmu16 that are homologous to Hsa21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb at 6 weeks 16 weeks showed distinctive abnormalities in BMD, trabecular architecture, and reduced bone strength over time that occur generally through an interaction between sex and genotype. Increased gene dosage and sexual dimorphism in Dp1Tyb mice revealed distinct phenotypes in bone formation and resorption. To assess how Dyrk1a influences the activity and function of osteoblasts Ts65Dn female trisomic mice, female mice with a floxed Dyrk1a gene (Ts65Dn, Dyrk1afl/+) were be bred to Osx1-GFP::Cre+ mice to generate Ts65Dn animals with a reduced copy of Dyrk1a in mature osteoblast cells. Female Ts65Dn,Dyrk1a+/+/+ and Ts65Dn,Dyrk1a+/+/-displayed significant defects in both trabecular architecture and cortical geometry. Ultimate force was reduced in trisomic animals, suggesting whole bone and tissue level properties are not adversely affected by trisomy. Reduction of Dyrk1a functional copy number in female mice did not improve skeletal deficits in an otherwise trisomic animal. Dyrk1a may not alter osteoblast cellular activity in an autonomous manner in trisomic female mice. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of the skeleton in DS mice, potentially paving the way for identification of the causal dosage-sensitive genes in both male and female animals.

Childhood acute leukemias are genetically complex disorders, with recurrent or random aberrations found in most patients. Their proper functional characterization is crucial for understanding the role they play in the process of leukemogenesis. We aimed to identify and characterize the genetic background of two leukemic entities. The transient myeloproliferative disorder (TMD) is a preleukemic condition that occurs in 10% of newborns with Down syndrome. Trisomy 21 together with in-utero gained mutations in the GATA1 gene are essential in TMD and represent an ideal "multi-hit" model to study leukemogenesis. We investigated an alternative pathogenic mechanism enabling TMD development in a confirmed absence of trisomy 21. Novel deletions in the GATA1 and JAK1 genes were described as potential drivers of this TMD. The deletion D65_C228 in GATA1 results in the expression of an aberrant isoform, which is predicted to lose transactivation potential and, more importantly, to partially lose the ability of recognizing physiological DNA binding sites, possibly triggering TMD alone. Our thorough characterization of JAK1 F636del questions its role in TMD development. Analysis of JAK/STAT signaling suggested decrease of kinase activity upon F636 loss. Cells harboring the aberrant JAK1 did not obtain cytokine-...

The primary aim of this study was to determine the effectiveness of array-based technology for detecting and quantifying the presence of mosaicism. This aim was achieved by studying individuals having mosaicism for Down syndrome. SNP arrays were performed on 13 samples from individuals with mosaicism for trisomy 21, 13 samples from individuals with normal chromosome 21complements (negative controls) and 5 samples from individuals with full or partial trisomy 21 (positive controls). In addition, BAC arrays were processed on 6 samples from individuals with mosaicism for trisomy 21, 3 negative controls and 1 positive control. These studies have shown that array-based technology is effective for detecting mosaicism that is present in 20% or more cells with the results being consistent for both platforms. We also demonstrated the strength of array-based technology to identify previously unrecognized chromosomal mosaicism. A second aim of this study was to gain insight regarding the effect that trisomy 21 has on telomere attrition and the frequency of chromosomal instability. This study provides the first reported measure of both chromosome-specific telomere lengths and the frequency of acquired chromosome abnormalities in trisomic cells and isogenic euploid cells obtained from the same individuals. A chromosome-specific telomere length assay was performed on lymphocytes obtained from 24 young individuals with mosaicism for Down syndrome. While differences in overall telomere signal intensities were observed between the euploid and trisomic cells within a person, strikingly similar profiles for chromosome-specific telomere intensities were observed between the cell types within a person. Analyses were also completed on lymphoblast samples obtained from 8 older individuals with mosaicism for Down syndrome, including 5 individuals without dementia and 3 individuals with dementia. In the older study subjects, a significant inverse correlation was observed between telomere length and the frequency of micronuclei, suggesting that telomeric shortening is leading to an increased frequency of chromosomal instability, possibly through dicentric chromosome formation. However, further studies of more individuals, especially additional analyses of older individuals, are needed. These future studies may help to identify genomic regions of interest and serve to inform investigators of potential candidate genes in the etiology of dementia.