Trisomy Of Chromosome Research Articles

Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells.

Trisomy of human chromosome 21 (T21) gives rise to Down syndrome (DS), the most frequent live-born autosomal aneuploidy. T21 triggers genome-wide transcriptomic alterations that result in multiple atypical phenotypes with highly variable penetrance and expressivity in individuals with DS. Many of these phenotypes, including atypical neurodevelopment, emerge prenatally. To enable in vitro analyses of the cellular and molecular mechanisms leading to the neurological alterations associated with T21, we created and characterized a panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs). We subsequently differentiated these iPSCs to generate a panel of neural progenitor cells (NPCs). Alongside characterizing genotype effects from T21, we found that T21 NPCs showed inter-individual variability in growth rates, oxidative stress, senescence characteristics, and gene and protein expression. Pathway enrichment analyses of T21 NPCs identified vesicular transport, DNA repair, and cellular response to stress pathways. These results demonstrate T21-associated variability at the cellular level and suggest that cell lines from individuals with DS should not solely be analyzed as a homogenous population. Examining large cohorts of genetically diverse samples may more fully reveal the effects of aneuploidy on transcriptomic and phenotypic characteristics in T21 cell types. A panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs) were created and subsequently differentiated into neural progenitor cells (NPCs). T21 NPCs showed reduced growth, increased oxidative stress, and inter-individual variability in gene and protein expression. This inter-individual variability suggests that studies with large cohorts of genetically diverse T21 samples may more fully reveal the effects of aneuploidy.

Abstract 4140108: A CRISPR-Activation CROP-seq Screen Identifies HMGN1 as a Dosage-Sensitive Regulator of Heart Defects in Down Syndrome

Introduction/Background: Congenital heart defects (CHD) are the most common form of developmental abnormalities, occurring in ~1% of live births, and can arise due to altered dosage of genes essential for cardiogenesis. Aneuploidy accounts for nearly 15% of CHD and the most frequent form involves trisomy of chromosome 21 (Ch21), resulting in Down Syndrome (DS). CHD is present in ~50% of DS cases, with a 1000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction of the atria and ventricles. Hypothesis: We hypothesize that the presence of a third copy of one or more genes on Ch21 underlies AVC and other cardiac defects; however, the dosage-sensitive CHD gene(s) on Ch21 causing this are not fully defined. Methods: We used human pluripotent stem cells derived from an individual mosaic for DS, allowing us to compare Ch21 trisomy cells with isogenic control cells disomic for Ch21. We performed single cell RNA-sequencing (scRNA-seq) to define the transcriptional dysregulation associated with DS in atrioventricular canal myocardial cells (AVCM). We then introduced a CRISPR-activation transgene to disomic cells and delivered small guide RNAs (sgRNAs) against 66 candidate Ch21 CHD genes. We developed a new machine learning algorithm to assign a trisomic score to CRISPR perturbed (CROP-seq) cells. Finally, we reduced the copy number of our top candidate gene in a mouse model of Down Syndrome and used microCT to assess incidence of cardiac septal defects. Results: Using human pluripotent stem cell and mouse models of DS, we identify HMGN1, a nucleosome-binding epigenetic factor on Ch21, as a dosage-sensitive regulator of cardiac defects in DS. Single cell transcriptomics revealed that human AVC cardiomyocytes shifted to a more ventricular myocardial state in trisomy 21 hiPS-derived cells. CRISPR-activation in isogenic disomic cells of 66 candidate Ch21 genes expressed in heart development, followed by single cell RNA-sequencing (CROP-seq) combined with machine learning predictions indicated that increased expression levels of HMGN1 altered the transcriptional state of atrioventricular cardiomyocytes similar to trisomy 21. Finally, reduction of Hmgn1 from three to two alleles in a mouse model of DS attenuated the incidence of cardiac septal defects. Conclusion: Our results identify HMGN1 as a dosage sensitive regulator of heart defects in DS and represent a generalizable approach for identifying candidate genes within areas of aneuploidy.

Use of Heber FERON as Part of the Treatment in Diffuse brain tumors: Report of Two Cases and Literature Review

Glioblastomas are the most common and malignant tumor among glial neoplasms (1). According to the Central Brain Tumor Registry of the United States (CBTRUS), the age-adjusted annual incidence rate of malignant primary brain tumors is 7.06/100,000 inhabitants and glioblastoma was 49.1% of them (2). It is characterized by being a fast-growing tumor, composed of a heterogeneous mixture of poorly differentiated astrocytic tumor cells, with pleomorphism, necrosis and vascular proliferation. According to the fifth classification of the World Health Organization, this type of tumor does not present a mutation in the IDH gene and usually presents a mutation in the EGFR gene, a mutation of the TERT promoter, trisomy of chromosome 7 and monosomy of chromosome 10 (3). It can manifest at any age, but it mainly affects adults, with a peak incidence between 45 and 70 years (3).The failure of current therapeutic approaches (focusing on surgical resection followed by radiotherapy and chemotherapy) is due to the dissemination that occurs in these tumors. Gliomas are highly infiltrating neoplasms, with solitary tumor cells or clusters of neoplastic cells that migrate extensively throughout the brain. In addition, malignant gliomas are an important stimulator of angiogenesis in a physiological manner, and angiogenesis in turn, may be a significant component in the progression of glial tumors. (5)This situation shows that the population of patients with malignant gliomas does not have therapeutic options to prolong their life, for this reason these two cases are presented to whom a therapeutic option with HeberFERON was offered to patients with diffuse brain tumors with a poor prognosis, also evaluating its antitumor effect (Imaging).

Trisomy 16 mimicking hydatidiform mole.

The authors present a case of 1st trimester miscarriage where an early, complete hydatidiform mole was clinically suspected. Histopathological and immunohistochemical analyses excluded a complete mole, but the histomorphological profile was in concordance with a partial hydatidiform mole. Genetic analysis excluded a partial mole based on biparental genome composition, where further genetic analyses detected trisomy of chromosome 16. Trisomy of chromosome 16 is a frequent cause of 1st trimester abortions and may lead to highly abnormal placental histomorphology mimicking a partial mole. Genetic analyses are crucial for proper differential diagnosis and for the determination of adequate follow-up and prognosis for further pregnancies.

Occurrence of high hyperdiploid karyotypes in childhood Acute Lymphoblastic Leukemia

Abstract Introduction/Objective High hyperdiploidy is defined as the non-random gain of chromosomes, increasing the modal chromosome number from 46 to between 51 and 65 or 67. This condition is the most common finding in childhood acute lymphoblastic leukemia, with a good outcome. It is generally characterized by the gain of chromosomes, typically X, 4, 6, 10, 14, 17, 18, and 21. The objective of this study is to determine the frequency of high hyperdiploidy in childhood ALL. Methods/Case Report Cytogenetic results of 435 patients, reported between October 2020 and September 2022 were reviewed retrospectively. All individuals were suspected for ALL between ages 1-15 years. Chromosomal analysis was performed in the Cytogenetics Lab of the Indus hospital and health network. Fluorescent in-situ hybridization (FISH) analysis were also carried out with probes for co-relating the gain of chromosomes. Results (if a Case Study enter NA) A total of 435 individuals were successfully karyotyped, 82 karyotypes showed hyperploidy without any additional abnormality, 213 patients showed hyperploidy along with additional structural aberrations, and 143 individuals showed normal karyotype. Among all the hyperploid karyotypes, chromosomes X, 4, 6, 10, 14, 17, 18, 21 were all gained in approximately 70% of the cases. Whereas, chromosome 21 was gained in 100% of all cases. FISH results also showed the gain of signals for particular probes including chromosomes 8, 9, 11, 12, 21 and 22. Conclusion In summary, this study leads to the fact that high hyperdiploidy is the most common abnormality in childhood acute lymphoblastic leukemia. It is assured that the occurrence of constituent trisomies of certain chromosomes is linked with the prognosis of the disease and also helps in determining the differences in treatment of the disease. Furthermore, correlation of karyotypes with the FISH results have also played a vital role in increasing the accuracy of results in this study.

Neurodevelopment in Young Children With Sex Chromosome Trisomies Diagnosed Before Birth: A Cluster Analysis Study.

Many studies have investigated the neuropsychological profile of individuals with sex chromosome trisomies (SCTs) and have identified some fragilities in language development within a wide individual variability. However, only a few studies have focused on children in the second year of life (12-24 months), a crucial stage for neurodevelopment. The present study aimed to identify and describe neurodevelopmental patterns in young children with SCTs. Seventy children with SCTs, ranging in age from 14 to 29 months, were administered the Griffiths Mental Development Scales, and their different neurodevelopmental profiles were identified using cluster analysis. Two-step cluster analysis highlighted two profiles of children equally distributed between groups. The two clusters showed a similar pattern but different levels of functioning, with children in Cluster 1 showing a lower performance in all the areas considered than children in Cluster 2. However, in both clusters, all the mean scores were in the normative range, with a significant gap in the linguistic area. Identifying the subgroups of young children with SCTs at higher risk can contribute to developing early monitoring protocols and targeted therapy approaches.

Odontogenic Myxomas Harbor Recurrent Copy Number Alterations and a Distinct Methylation Signature.

Odontogenic myxoma is a rare, benign, and locally aggressive tumor that develops in the tooth-bearing areas of the jaw. The molecular mechanisms underlying odontogenic myxomas are unknown and no diagnostic markers are available to date. The aim of this study was to analyze DNA methylation and copy number variations in odontogenic myxomas to identify new molecular signatures for diagnostic decision-making. We collected a cohort of 16 odontogenic myxomas from 2006 to 2021 located in the mandible (n = 10) and maxilla (n = 6) with available formalin-fixed paraffin-embedded or fresh frozen tumor tissue from a biopsy or resection material. Genome-wide DNA methylation and copy number variation data were generated from 12 odontogenic myxomas using the Illumina Infinium Methylation EPIC array, interrogating >850,000 CpG sites. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that odontogenic myxomas formed a distinct DNA methylation class. Copy number profiling showed recurrent whole-chromosome gains (trisomies) of chromosomes 5, 8, and 20 in all cases, and of chromosomes 10, 12, and 17 in all except one case. In conclusion, odontogenic myxomas harbor recurrent copy number patterns and a distinct DNA methylation profile, which can be used as an additional diagnostic tool in the appropriate clinical and radiologic context. Further research is needed to explain the genetic mechanisms caused by these alterations that drive these locally aggressive neoplasms.

Comprehensive Assessment of Dermatologic and Dysmorphic Manifestations in Patients With Down Syndrome.

Down syndrome (DS), a common chromosomal anomaly caused by trisomy of chromosome 21, is characterized by a broad spectrum of phenotypic characteristics across multiple organ systems, including cardiac defects and leukemia. Dermatological findings are prevalent among individuals with DS; however, these issues are frequently underrecognized and inadequately researched, resulting in a significant gap in the provision of comprehensive healthcare strategies. Given the increased life expectancy of patients with DS and delayed manifestation of many dermatoses, physicians are increasingly encountering dermatological findings in this population. This study aimed to assess the prevalence and types of dermatological findings in individuals with DS, compare them with those in a control group, and emphasize the necessity of incorporating dermatological evaluations into routine health monitoring. This prospective cross-sectional study was conducted from June 2023 to June 2024 and involved 100 genetically confirmed individuals with DS and 100 age- and sex-matched controls. Comprehensive demographic, clinical, and karyotype data were collected for the DS group, and all the participants underwent detailed morphological evaluations. The DS group had a mean age of approximately 6.37 years, whereas the controls were around 7 years old, with no significant differences in age or sex distribution between the groups. Karyotype analysis showed that trisomy 21 was present in 92% of the cases, mosaicism in 6%, and translocation in 2%. Common dermatological findings in the DS group included xerosis cutis (49%), thin and sparse hair (48%), dental caries (34%), delayed tooth eruption (28%), nail dystrophy (25%), fissured tongue (23%), and cheilitis (18%). Significant differences were noted in the prevalence of scabies, bacterial infections, and café au lait macules between the DS and control groups (p < 0.01). Dysmorphic findings in the DS group included epicanthal folds (97%), upslanted palpebral fissures (97%), brachycephaly (91%), and single transverse palmar crease (89%). Significant gender differences were noted in the prevalence of brachycephaly and the sandal gap (p < 0.01). This study highlights the importance of regular dermatological care in enhancing the health management and quality of life of individuals with DS due to the prevalence and variability of dermatological conditions.

Temporal Genomic Dynamics Shape Clinical Trajectory in Multiple Myeloma.

To comprehensively unravel the temporal relationship between initiating and driver events and its impact on clinical outcomes, we analyzed 421 whole-genome sequencing profiles from 382 patients. Using clock-like mutational signatures, we estimated a time lag of 2-4 decades between initiating events and diagnosis. In patients with hyperdiploidy, we demonstrate that trisomies of odd-numbered chromosomes can be acquired simultaneously with other chromosomal gains, such as 1q gain. We provide evidence that hyperdiploidy is acquired after canonical IGH translocation when both events are present. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra-copies), but faring worse than those with late 1q gain. This underscores that the prognostic impact of 1q gain/amp depends more on the timing of acquisition than on the number of extra copies gained. Overall, this study contributes to a better understanding of the life history of MM and may have prognostic implications.

Patient-derived tau and amyloid-β facilitate long-term depression in vivo: role of tumour necrosis factor-α and the integrated stress response.

Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. In vivo electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease.

Health comorbidities in children with down syndrome (DS) at Dr. Sardjito General Hospital, Yogyakarta

Down syndrome (DS) is a disease caused by trisomy of chromosome 21. The phenotype in DS leads to manifestations in several organ systems. This study aimed to identify the pattern of comorbidities in DS patients. It was a single-center, cross-sectional study at Dr. Sardjito General Hospital, Yogyakarta. Medical records of pediatric patients with DS from a period of January 2022 to May 2023 were included. Descriptive analysis was performed to demonstrate demographic and clinical characteristics. A total of 355 pediatric patients with DS were found at Dr. Sardjito General Hospital and the majority were male (196 children or 55.2%). As much as 339 children (95.49%) had comorbidities. The highest comorbidity was congenital heart disease (230 patients or 67.84%) in specifics were atrial septal defect (41 patients or 12.39%), atrioventricular septal defect (29 patients or 8.17%), and patent ductus arteriosus (28 patients or 7.88%). The second highest comorbidity was endocrine system disorders (102 patients or 30.09%), with 100 patients (28.16%) children suffering hypothyroidism. The number of children who had one comorbidity was 248 patients (69.86%), 74 patients (20.48%) had two comorbidities, and 17 patients (4.79%) had three or more comorbidities. The highest co-prevalence of the two comorbidities was congenital heart disease and endocrine system disorders (36 patients or 10.14%). The highest co-prevalence of 3 or more comorbidities was a combination of congenital heart disease, visual impairment, and hearing impairment (6 patients or 1.69%). In conclusion, 95.49% of children with DS have comorbidities. The most common comorbidity was heart defects. About 25.63% of patients had more than one comorbidity. Children with DS who have comorbidities require more attention to prevent complications and to reduce morbidity.

Network Pharmacology Identifies Intersection Genes of Apigenin and Naringenin in Down Syndrome as Potential Therapeutic Targets.

Down Syndrome (DS), characterized by trisomy of chromosome 21, leads to the overexpression of several genes contributing to various pathologies, including cognitive deficits and early-onset Alzheimer's disease. This study aimed to identify the intersection genes of two polyphenolic compounds, apigenin and naringenin, and their potential therapeutic targets in DS using network pharmacology. Key proteins implicated in DS, comprising DYRK1A, APP, CBS, and ETS2, were selected for molecular docking and dynamics simulations to assess the binding affinities and stability of the protein-ligand interactions. Molecular docking revealed that naringenin exhibited the highest binding affinity to DYRK1A with a score of -9.3 kcal/mol, followed by CBS, APP, and ETS2. Moreover, molecular docking studies included positive control drugs, such as lamellarin D, valiltramiprosate, benserazide, and TK216, which exhibited binding affinities ranging from -5.5 to -8.9 kcal/mol. Apigenin showed strong binding to APP with a score of -8.8 kcal/mol, suggesting its potential in modulating amyloid-beta levels. These interactions were further validated through molecular dynamics simulations, demonstrating stable binding throughout the 100 ns simulation period. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses indicated minimal fluctuations, confirming the stability of the complexes. The findings suggest that apigenin and naringenin could serve as effective therapeutic agents for DS by targeting key proteins involved in its pathology. Future studies should focus on in vivo validation, clinical trials, and exploring combination therapies to fully harness the therapeutic potential of these compounds for managing DS. This study underscores the promising role of network pharmacology in identifying novel therapeutic targets and agents for complex disorders like DS.

Quantifying the Spectrum of Early Motor and Language Milestones in Sex Chromosome Trisomy.

Sex chromosome trisomy (SCT) is a common chromosomal abnormality associated with increased risks for early developmental delays and neurodevelopmental disorders later in childhood. Our objective was to quantify the spectrum of early developmental milestones in SCT. We hypothesized later milestone achievement in SCT than the general population. Data were collected as part of the eXtraordinarY Babies Study, a prospective natural history of developmental and health trajectories in a prenatally identified sample of infants with SCT. Parent reported, clinician-validated, early motor and language milestones were collected at 2, 6, 12, 18, 24, and 36-months. Age distributions of milestone achievement were compared with normative data. In all SCT conditions, compared with normative data, there was increased variability and a later median age of skill development across multiple gross motor and expressive language milestones. Results also show a significant amount of overlap with the general pediatric population, suggesting that for many children with prenatally identified SCT, early milestones present within, or close to, the expected timeline. As increasing numbers of infants with prenatal SCT diagnoses present at pediatric practices, we provide an evidence-based schedule of milestone achievement in SCT as a tool for pediatricians and families. Detailed data on SCT milestones can support clinical interpretation of milestone achievement. Increased variability and later median age of milestone acquisition in SCT compared to norms support consideration of all infants with SCT as high risk.

General Dietary Recommendations for People with Down Syndrome.

Down syndrome (DS) is caused by trisomy of chromosome 21 and is associated with characteristic features of appearance, intellectual impairment to varying degrees, organ defects, and health problems typical of this syndrome. Studies on the frequency of consumption of food products in this group show many irregularities, in particular too low consumption of vegetables and fruits, wholegrain cereal products and dairy products, and excessive consumption of meat products and sweets. It is necessary to correct eating habits. The diets of people with trisomy 21 should be consistent with the recommendations of rational nutrition for the general population and take into account specific dietary modifications related to the occurrence of diseases and health problems characteristic of this syndrome.

Ketoconazole induces reversible antifungal drug tolerance mediated by trisomy of chromosome R in Candida albicans.

The emergence of tolerance to antifungal agents in Candida albicans complicates the treatment of fungal infections. Understanding the mechanisms underlying this tolerance is crucial for developing effective therapeutic strategies. This study aims to elucidate the genetic and molecular basis of ketoconazole tolerance in C. albicans, focusing on the roles of chromosomal aneuploidy, Hsp90, and calcineurin. The wild-type C. albicans strain SC5314 was exposed to increasing concentrations of ketoconazole (0.015-32 μg/mL) to select for tolerant adaptors. Disk diffusion and spot assays were used to assess tolerance. Whole-genome sequencing identified chromosomal changes in the adaptors. The roles of Hsp90 and calcineurin in maintaining and developing ketoconazole tolerance were investigated using specific inhibitors and knockout strains. Adaptors exhibited tolerance to ketoconazole concentrations up to 16 μg/mL, a significant increase from the parent strain's inhibition at 0.015 μg/mL. All tolerant adaptors showed amplification of chromosome R, with 29 adaptors having trisomy and one having tetrasomy. This aneuploidy was unstable, reverting to euploidy and losing tolerance in drug-free conditions. Both Hsp90 and calcineurin were essential for maintaining and developing ketoconazole tolerance. Inhibition of these proteins resulted in loss of tolerance. The efflux gene CDR1 was not required for the development of tolerance. Chromosome R trisomy and tetrasomy induce cross-tolerance to other azole antifungal agents, including clotrimazole and miconazole, but not to other antifungal classes, such as echinocandins and pyrimidines, exemplified by caspofungin and 5-flucytosine. Ketoconazole tolerance in C. albicans is mediated by chromosomal aneuploidy, specifically chromosome R amplification, and requires Hsp90 and calcineurin. These findings highlight potential targets for therapeutic intervention to combat antifungal tolerance and improve treatment outcomes.

Prosody in narratives: An exploratory study with children with sex chromosomes trisomies

Although language delays are common in children with sex chromosome trisomies [SCT], no studies have analysed their prosodic abilities. Considering the importance of prosody in communication, this exploratory study aims to analyse the prosodic features of the narratives of 4-year-old children with SCT.Participants included 22 children with SCT and 22 typically developing [TD] children. The Narrative Competence Task was administered to elicit the child's narrative. Each utterance was prosodically analysed considering pitch and timing variables.Considering pitch, the only difference was the number of movements since the utterances of children with SCT were characterised by a lower speech modulation. However, considering the timing variables, children with SCT produced a faster speech rate and a shorter final syllable duration than TD children.Since both speech modulation and duration measures have important syntactic and pragmatic functions, further investigations should deeply analyse the prosodic skills of children with SCT in interaction with syntax and pragmatics.

Dissecting the contribution of human chromosome 21 syntenic regions to recognition memory processes in adult and aged mouse models of Down syndrome.

Trisomy of human chromosome 21 (Hsa21) results in a constellation of features known as Down syndrome (DS), the most common genetic form of intellectual disability. Hsa21 is orthologous to three regions in the mouse genome on mouse chromosome 16 (Mmu16), Mmu17 and Mmu10. We investigated genotype-phenotype relationships by assessing the contribution of these three regions to memory function and age-dependent cognitive decline, using three mouse models of DS, Dp1Tyb, Dp(17)3Yey, Dp(10)2Yey, that carry an extra copy of the Hsa21-orthologues on Mmu16, Mmu17 and Mmu10, respectively. Prior research on cognitive function in DS mouse models has largely focused on models with an extra copy of the Mmu16 region and relatively little is known about the effects of increased copy number on Mmu17 and Mmu10 on cognition and how this interacts with the effects of aging. As aging is is a critical contributor to cognitive and psychiatric changes in DS, we hypothesised that ageing would differentially impact memory function in Dp1Tyb, Dp(17)3Yey, and Dp(10)2Yey, models of DS. Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Our results show that distinct Hsa21-orthologous regions contribute differentially to cognitive dysfunction in DS mouse models and that aging interacts with triplication of Hsa21-orthologous genes on Mmu10.

Medical Findings in Infants Prenatally Identified with Sex Chromosome Trisomy in Year One of Life.

Sex chromosome trisomies (SCT), including XXY, XYY, and XXX syndromes, have been historically underdiagnosed. Noninvasive prenatal cell-free DNA screening has significantly increased identification of these conditions, leading to a need for pediatric care for a growing population of newborns with SCT. Our goal was to analyze and compare perinatal features, medical diagnoses, and physical features in infants with prenatal identification of SCT conditions through the first year of life. The eXtraordinarY Babies Study is an ongoing, prospective natural history study of prenatally identified children with SCT conducted by interdisciplinary teams in Colorado and Delaware. Participants were enrolled prior to 12 months of age and had pregnancy, birth, medical histories, and physical exams completed by board-certified pediatricians at 2, 6, and/or 12-month visits. Descriptive statistics were followed by comparisons between SCT groups using t-tests or ANOVA, Fisher exact, and correlations between medical features with alpha of 0.05. Relative risks were calculated compared to general population rates. 327 infants were included in the analysis (XXY=195, XXX=79, XYY=53). Major congenital anomalies were rare (1.7%). Relative risk compared to general population was elevated for breastfeeding difficulties (51.7%;RR 2.7), positional torticollis (28.2%;RR 7.2), eczema (48.0%;RR 3.5), food allergies (19.3%;RR 2.4), constipation requiring intervention (33.9%;RR 7.6), small cardiac septal defects (7.7%;RR 17.2), and structural renal abnormalities (4.4%;RR 9.7). Inpatient hospitalization was required for 12.4%, with 59.5% of hospitalizations attributable to respiratory infections. These findings of medical conditions with a higher prevalence can inform anticipatory guidance and medical management for pediatricians caring for infants with SCT. Medical findings in largest cohort of prenatally identified infants with XXY, Trisomy X, and XYY from birth to 12 months and implications for pediatric care.What's Known on This Subject: One in ∼500 individuals have an extra X or Y chromosome, or sex chromosome trisomy (SCT). Prenatal screening is now routinely identifying SCT, however there are few studies to guide perinatal and infant care for these individuals.What This Study Adds: This prospective observational study presents medical features for 327 infants with prenatally identified SCT from birth through the first year of life. Results identify where proactive screenings and/or interventions may be warranted for infants with SCT.

Congenital syndromic Chiari-like malformation (CSCM) in Holstein cattle: towards unravelling of possible genetic causes

BackgroundChiari malformation type II (CMII) was originally reported in humans as a rare disorder characterized by the downward herniation of the hindbrain and towering cerebellum. The congenital brain malformation is usually accompanied by spina bifida, a congenital spinal anomaly resulting from incomplete closure of the dorsal aspect of the spinal neural tube, and occasionally by other lesions. A similar disorder has been reported in several animal species, including cattle, particularly as a congenital syndrome. A cause of congenital syndromic Chiari-like malformation (CSCM) in cattle has not been reported to date. We collected a series of 14 CSCM-affected Holstein calves (13 purebred, one Red Danish Dairy F1 cross) and performed whole-genome sequencing (WGS). WGS was performed on 33 cattle, including eight cases with parents (trio-based; group 1), three cases with one parent (group 2), and three single cases (solo-based; group 3).ResultsSequencing-based genome-wide association study of the 13 Holstein calves with CSCM and 166 controls revealed no significantly associated genome region. Assuming a single Holstein breed-specific recessive allele, no region of shared homozygosity was detected suggesting heterogeneity. Subsequent filtering for protein-changing variants that were only homozygous in the genomes of the individual cases allowed the identification of two missense variants affecting different genes, SHC4 in case 4 in group 1 and WDR45B in case 13 in group 3. Furthermore, these two variants were only observed in Holstein cattle when querying WGS data of > 5,100 animals. Alternatively, potential de novo mutational events were assessed in each case. Filtering for heterozygous private protein-changing variants identified one DYNC1H1 frameshift variant as a candidate causal dominant acting allele in case 12 in group 3. Finally, the presence of larger structural DNA variants and chromosomal abnormalities was investigated in all cases. Depth of coverage analysis revealed two different partial monosomies of chromosome 2 segments in cases 1 and 7 in group 1 and a trisomy of chromosome 12 in the WDR45B homozygous case 13 in group 3.ConclusionsThis study presents for the first time a detailed genomic evaluation of CSCM in Holstein cattle and suggests an unexpected genetic and allelic heterogeneity considering the mode of inheritance, as well as the type of variant. For the first time, we propose candidate causal variants that may explain bovine CSCM in a certain proportion of affected calves. We present cattle as a large animal model for human CMII and propose new genes and genomic variants as possible causes for related diseases in both animals and humans.

P-518 Differentially gene expression identified by RNA seq in aneuploid human blastocysts is more influenced by the phenomenon of aneuploidy than the involved chromosome

Abstract Study question What insights do RNA-Seq profiles provide about gene expression in aneuploid blastocysts with small and large chromosomes compared to euploid blastocysts? Summary answer The difference in gene expression is affected by aneuploidy and is more related to the presence of aneuploidy than the size of the aneuploid chromosomes. What is known already Embryonic aneuploidy is one of the main common causes of implantation failure and miscarriage. RNA-Seq investigations of the embryo in the early stages of preimplantation indicate that with the gradual replacement of the embryonic profile and the reduction of the oocyte residues, the gene expression profile in the blastocyst is more dependent on the embryo’s genome. A recent study by comparing the gene expression profile of euploid blastocysts and specific aneuploidies such as trisomy 21, trisomy 18, XXY and XO syndromes using RNA-Seq, showed how the type of aneuploidy might affect gene expression. Study design, size, duration This study was conducted on surplus embryos of the patients with history of recurrent implantation failure or recurrent miscarriage following PGT by Day-5 trophectoderm biopsy. Inclusion criteria involved maternal age ≤37, normal parental karyotypes, and ovulation by long stimulation protocol. As advanced maternal age and ovarian stimulation method can affect the aneuploidy rate and expression profile, embryos belonging to mothers &amp;gt; 37 years and included only patients with the long stimulation protocol were excluded. Participants/materials, setting, methods The normal embryos and those with single aneuploidy were selected for comparison of gene expression profiles using RNA sequencing. The single aneuploid embryos were classified in two groups: with defined aneuploidy(DA) of small chromosomes (including chromosomes 16, 20, 21, 22), and with undefined aneuploidy(UA) as single aneuploids for other chromosomes. To neutralize the effect of genomic content on gene expression profile in DA group, embryos were pooled reciprocally (trisomy and monosomy for the same chromosome). Main results and the role of chance Principal Component Analysis (PCA) validated embryos classification considering their differentially expressed genes (DEG) clustering into three distinct groups. To minimize the role of chance, only genes with significant adjusted P-values in both STAR and Hisat data analyses were included in consequent interpretations. In addition to comparison between and among the DA, UA and normal groups, the entire set of aneuploid groups was compared with the normal group. The DEG in both aneuploid groups compared to the normal group represented eminent upregulation rather than downregulation. Gene Ontology analyses indicated an upregulation of transcription, ubiquitination, autophagy, mitochondrial, chromosome segregation and DNA repair pathways in both DA and UA compared to normal group. Overexpression of the DNA repair pathway and other validated genes of interest in aneuploid embryos was in agreement with qPCR findings. Translation and protein synthesis pathways also showed overexpression as part of the functional response to aneuploidy. Upregulation of apoptotic process pathway was evident in the UA group. While comparison of gene expression between DA and UA showed overexpression of 143 genes, but cellular lipid synthesis was the only pathway with a significant difference. The distribution of DEG on chromosomes in the DA group was not associated with selected aneuploidies. Limitations, reasons for caution The number of biological replicates in each category was limited in order to provide more confident data by minimizing the time interval between providing the samples and RNA sequencing. Larger studies might change some affected pathways due to differences in identified DEG. Wider implications of the findings This study shed light on the black box of human preimplantation aneuploidy. Considering that the transcriptome is affected by the genomic status and some debates on genomic based current PGT approaches, this study is a step for selection of healthy and viable embryos by revealing the molecular mechanisms. Trial registration number not applicable