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.

Down syndrome (DS) is a developmental disorder caused by a triplication of human chromosome 21, which contains approximately 550 genes. DS is the most common autosomal aneuploidy occurring with an incidence of 1 in 793 live births. Hallmarks of DS include abnormal central nervous system (CNS) development and function resulting in intellectual disability (ID), motor dysfunction, and early onset Alzheimer’s neuropathology. Studies have elucidated widespread neurohistological abnormalities in brains of fetuses with DS as early as 20 weeks of gestation, suggesting that early dysfunction in neural development may set the stage for exacerbated CNS abnormalities throughout life. Additionally, the complex constellation of symptoms associated with DS changes over the lifespan, particularly in adolescence and in middle to old age. Thus, these periods may represent opportune windows for age-specific therapeutic interventions. Due to ethical and practical constraints, use of human samples is alone insufficient to characterize the etiological underpinnings of DS phenotypes across the lifespan. Furthermore, while human data are instructive for drug development, preclinical trials are necessary for target validation, to establish dosage, and to prove safety and efficacy of any proposed therapeutic. With the advent of mouse models of DS, informative studies on the neurobiology of DS as well as preclinical testing of proposed therapies are possible. Here, we use a multi-pronged approach to assess molecular, neuroanatomical, and behavioral phenotypes indicative of brain and SC function in three distinct mouse models of DS: Ts1Cje, Ts65Dn, and Dp16. We identify neurodevelopment phenotypes, cytoarchitectural aberrations, bioenergetic abnormalities, myelination deficits, and motor/cognitive dysfunction at multiple ages spanning the period between embryonic day 12.5 and 6-7 months in trisomic mice. Additionally, we show that while Ts65Dn mice recapitulate all known phases of histological, functional, and behavioral phenotypes typical of DS starting from prenatal development and into middle age, this is not true for the Ts1Cje or Dp16 models. Lastly, we present promising outcomes of two possible therapies for cognitive and motor dysfunction in Ts65Dn mice. Altogether our findings provide insights into the underlying neurobiology of ID and motor dysfunction in DS and elucidate molecular changes that can be targeted for future therapeutic intervention. / 2018-07-09T00:00:00Z

Individuals with Down syndrome (US) suffer from increased incidence of respiratory infections and lymphoblastic leukemia, and a death rate that is particularly high in the first 5 years of life. Relatively few studies have probed immune parameters in young US children. Primary immune defects in DS may be masked by a degree of immune maturity in adults, and hygienic factors may have an effect on immune capability throughout the years. A study of young children can give clearer evidence of the actual primary immune defects in DS. Blood samples were drawn from 20 DS children under 6 years old and from age-matched controls. Packed blood cell volume was measured, various blood cell subpopulations were enumerated and differential counts were performed. Several tests of cellular immune function were performed and plasma zinc levels were determined using atomic adsorption spectrophotometry. Elevated hematocrit levels were observed in the US group. White blood cell counts and proportions of rosette-forming cells were normal in blood from DS children. Altered neutrophil and lymphocyte proportions in DS samples resulted from a depressed number of circulating lymphocytes in the these subjects. This indicated that T cell numbers are low in DS. DS individuals had a low number of circulating OKT4+ T cells which resulted in significantly depressed T4:T8 ratios. Cells from DS subjects exhibited a reduced proliferative response to phytohemagglutinin; a low response to the optimal concentration of concanavalin A was seen with DS samples, but at suboptimal doses the response was normal; suboptimal concentrations of pokeweed mitogen elicited normal responses by cells from DS children. Preliminary results suggest that interleukin-2 (IL-2) production in young children may correlate positively with age and that DS subjects may produce normal or elevated amounts of IL-2. This suggests that IL-2 receptor function may be defective in T cells from DS children. DS children had normal natural killer cell activity and cells from those children were no more sensitive to the augmenting effects of interferon-alpha than cells from control children. Plasma zinc levels in DS appeared to be normal. These findings not only provide evidence that the primary immune defect in DS involves low levels of T cells, but they show depressed number and function of helper T cells and suggest defective IL-2 receptor expression in DS.

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.

Although called by our vocation and the mission of Catholic schools, students with disabilities (SWD) are underserved in Catholic education. Only approximately 1% of the nation’s SWD population (67,000 students) attend private schools with 40% identified as Catholic (U.S. Department of Education, 2018a). Despite the small number, SWD and peers that struggle are attending our schools and therefore, must be included meaningfully and served successfully. This study dispels the myths around the admission and service of students with Down syndrome in Catholic schools and informs educational leaders on how to create and sustain inclusive environments aligned with Catholic Social Teachings. A qualitative research approach comprising semi-structured interviews and document review was used in the study. The framework of Catholic social teachings and the epistemology of inclusivity were used to get answers to the two research questions: (a) how does a Catholic elementary school serve students with Down syndrome? and (b) What are the challenges in serving students with Down syndrome in a Catholic elementary school? The significance of this case study lies in witnessing and documenting one elementary Catholic school’s experience of creating, developing, establishing, and modeling an inclusion environment that serves the needs of its students with Down syndrome. This study ultimately provides data to those in similar Catholic school settings in developing and implementing fully inclusive environments. This study further expands the discussion in the field of Catholic education about the right(s) of all Catholic children, especially students with Down syndrome.

Due to their underlying genetic complexity, chromosomal disorders such as Down syndrome (DS), which is caused by trisomy 21, have long been understudied and continue to lack effective treatments. With over 200 genes on the extra chromosome, even the specific cell pathologies and pathways impacted in DS are not known, and it has not been considered a viable target for the burgeoning field of gene therapy. Recently, our lab demonstrated that the natural mechanism of dosage compensation can be harnessed to silence the trisomic chromosome in pluripotent cells. Using an inducible XIST transgene allows us to study the effects of trisomy in a tightly controlled system by comparing the same cells with either two or three active copies of chromosome 21. In addition, it raises the prospect that insertion of a single gene into a trisomic chromosome could potentially be developed in the future for “chromosome therapy”. This thesis aims to utilize this inducible system for dosage compensation to study the neurodevelopmental effects of trisomy 21 in vitro, and to answer basic epigenetic questions critical to the viability of chromosome silencing as a therapeutic approach. Foremost, for XIST to have any prospect as a therapeutic, and to strengthen its experimental utility, it must be able to initiate chromosome silencing beyond its natural context of pluripotency. Here I demonstrate that, contrary to the current literature, XIST is capable of initiating chromosome silencing in differentiated cells and producing fully dosage compensated DS neurons. Additionally, I show that silencing of the trisomic chromosome in neural stem cells enhances their terminal differentiation to neurons, and transcriptome analysis provides evidence of a specific pathway involved. Separate experiments utilize novel three-dimensional organoid technology and transcriptome analysis to model DS neurodevelopment in relation to isogenic euploid cells. Overall, this work demonstrates that dosage compensation provides a powerful experimental tool to examine early DS neurodevelopment, and establishes that XIST function does not require pluripotency, thereby overcoming a perceived obstacle to the potential of XIST as a therapeutic strategy for trisomy.

The purpose of this thesis is to investigate the link between advanced paternal ages (APA) (i.e., APA ≥ 35 years and APA ≥ 50 years) and genetic diseases and congenital anomalies. Currently, the relationship between both advanced paternal ages and genetic diseases and congenital anomalies remains unclear. However, there is room for improvement to systematically investigate the relationship between specific congenital anomalies in newborns and advanced paternal ages. More recently, the link between advanced paternal age (as opposed to existing studies analyzing advanced maternal age alone) and genetic diseases has been recognized by researchers, epidemiologists, and various health experts. Thus, this study serves to examine the effect of advanced paternal ages on the likelihood of birth defects using a new dataset intended to discover those relationships. I create three different datasets and utilize 12 statistical models to analyze the relationship between advanced paternal ages (APA ≥ 35 years and APA ≥ 50 years) (while including advanced maternal age or AMA [AMA ≥ 35 years]) and genetic diseases and congenital anomalies. I focus on Down syndrome, cleft lip with or without cleft palate, and meningocele/spina bifida and explore the relationship between both advanced parental ages. I explore whether (a) the advanced paternal ages and (b) the advanced maternal age increase the likelihood of newborn reproductive defects: (a) Down syndrome, (b) cleft lip with or without cleft palate, and (c) meningocele/spina bifida. This study includes all U.S. births between 2016 and 2019 using the CDC Natality Registry[1] database (2020). I perform the analyses using logistic regression models (to estimate odds ratios) that provide explanations of the relationship between each birth defect and advanced paternal ages. Analysis results suggest that advanced paternal ages (APA ≥ 35 years and APA ≥ 50 years) are positively associated with Down syndrome, whereas advanced paternal age (APA ≥ 35 years) is negatively associated with cleft lip with or without cleft palate. The results from the advanced paternal ages models do not suggest any causal relationship/effect on spina bifida. The results of this study are expected to offer some insight of the following reproductive defects: (a) Down syndrome, (b) cleft lip with or without cleft palate, and (c) meningocele/spina bifida. [1] Collection of data for all variables used in this research are obtained with full permission from: United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention" "(CDC), National Center for Health Statistics (NCHS), Division of Vital Statistics, Natality public-use data 2016-2019, on CDC" WONDER Online Database, October 2020. Accessed at http://wonder.cdc.gov/natality-expanded-current.html on Jun 6, 2021, 1:24:47 PM;" United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention" "(CDC), National Center for Health Statistics (NCHS), Division of Vital Statistics, Natality public-use data 2016-2019, on CDC" "WONDER Online Database, October 2020. Accessed at http://wonder.cdc.gov/natality-expanded-current.html on Jun 6, 2021, 1:29:36 PM;" And United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention""(CDC), National Center for Health Statistics (NCHS), Division of Vital Statistics, Natality public-use data 2016-2019, on CDC" "WONDER Online Database, October 2020. Accessed at http://wonder.cdc.gov/natality-expanded-current.html on Jun 6, 2021, 1:07:36 PM."

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