Search Results (267)

Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer’s disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD. Full article

Hypoplastic or absent fetal nasal bone (NB) is a significant soft marker in the risk assessment for aneuploidies. This study aimed to evaluate prenatal findings and perinatal outcomes in fetuses with absent or hypoplastic NB managed at our center. This retrospective analysis was conducted at the Department of Obstetrics at the Medical University of Vienna and including all cases with an absent or hypoplastic fetal NB between 2004 and 2022. Clinical data were extracted and analyzed using descriptive statistics. A total of 149 cases were included. Of these, 51% had chromosomal abnormalities, with trisomy 21 present in 30.9%. Malformations were identified in 55% of cases, most commonly congenital heart defects (34.9%) and facial dysmorphism (28.9%). Eighteen fetuses (12.1%) had structural anomalies without genetic disorders. In 32.9% (n = 49), the NB anomaly was isolated. Our findings show that only half of the cases had chromosomal abnormalities, and over half of the pregnancies resulted in live births with generally favorable perinatal outcomes. However, the presence of additional ultrasound abnormalities significantly increased the risk of adverse outcomes. Therefore, detection of a fetal NB anomaly should prompt comprehensive ultrasound evaluation and genetic testing. Full article

Background: In childhood acute lymphoblastic leukemia (ALL), in addition to classical chromosomal abnormalities, loss of heterozygosity (LOH), including copy-neutral LOH, is also observed. While LOH has been described in the literature, its clinical relevance in pediatric ALL remains unclear. The aim of this study is to identify and analyze patterns of LOH, assess their frequency, and evaluate their association with clinical characteristics and early treatment response during the induction phase of the ALL protocol. Methods: The study included 853 pediatric ALL patients, of whom 120 had B-ALL LOH+ and 58 had T-ALL LOH+. LOH was analyzed using CytoScan HD SNP microarrays. Patients were stratified using multiple correspondence analysis (MCA) and hierarchical clustering on principal components (HCPC), which identified three genetically and clinically distinct clusters. Results: In B-ALL, two clusters with extensive LOH—particularly involving chromosome 9—were associated with poor prognosis and suboptimal response to therapy. In contrast, Cluster 2, characterized by CDKN2A duplication and rare LOH, showed a favorable clinical course. In T-ALL, Cluster 1 had LOH in CDKN2A but favorable outcomes; Cluster 2 exhibited biallelic CDKN2A deletion and aggressive disease; Cluster 3 lacked CDKN2A alterations and showed a genetically stable profile. LOH was common on chromosomes not typically affected by trisomy and rare on those gained. Conclusions: Our study indicates that LOH profiling can positively influence patient stratification by identifying high-risk subgroups, inform prognosis by highlighting unfavorable genetic alterations, and help predict poor treatment response in specific clinical profiles. Full article

Background/Objectives: Ring chromosomes (RCs) can be rare or common depending on the chromosome involved. With interest in the historical RCs identified by our laboratory, we curated instances to provide further information to this research field. Methodology: We carried out a retrospective, single-center study of constitutional RCs identified starting in the late 1980s. Details for 40 RCs with a modal number of 46 chromosomes are featured here. Results: Mosaic and non-mosaic RCs are identified, with a preponderance of pediatric-aged females at first ascertainment. We corroborated an enrichment for acrocentric and X chromosome RCs. Six were ascertained perinatally, with peripheral blood being the most commonly studied postnatal specimen type. Notable RCs included a female fetus with an increased risk for monosomy X, whose mosaic RCY arose secondary to a translocation between the sex chromosomes. In another, a series of complex events formed three structurally aberrant chromosomes, including an RC4 with loss of 4p16.3, corresponding with the observed phenotypic expression of Wolf–Hirschhorn syndrome. In another, a mosaic RCX was co-identified with an isochromosome 21q, resulting in a dual diagnosis of trisomy 21 and Turner syndrome. In another, the atypical RC21 structure raises the possibility of a complex rearrangement. Chromosomal microarray data clarified breakpoints and gene dosage imbalances in fifteen, while low-level mosaicism for the RC escaped detection by array in another. Eight RCs were de novo, and parental exclusion was documented for six. Conclusions: This study illustrates the need for cytogenomic follow-up to improve the literature for patients with RCs. Full article

Autosomal trisomy, a genetic disorder characterized by the presence of an extra autosome, is a rare but important chromosomal abnormality in horses, often associated with infertility, developmental abnormalities, and reduced life expectancy. This study represents the largest population-level screening for autosomal trisomy in horses; the analysis used single nucleotide polymorphism (SNP) panel genotype intensity data from 17,078 horses, 6601 of which were juveniles (i.e., ≤12 months of age) when genotyped. Using methodologies adapted from similar screening studies in cattle, the only aneuploidy detected was trisomy 27 in two juvenile male Irish Sport Horses (ISH) (0.03% prevalence among juveniles or 0.01% prevalence in the overall population). One ISH colt was cytogenetically confirmed and displayed no overt external phenotypic abnormalities, while cytogenetics was not undertaken on the other ISH colt, nor was it phenotypically assessed. Parentage analysis revealed that one ISH colt inherited two different copies of chr27 from the sire, demonstrating heterodisomy, likely due to a nondisjunction event during meiosis I in the sire. The other ISH colt inherited two different copies of chr27 from the dam, also indicating heterodisomy; the dam was 23 years of age when the colt was born. Based on the observed prevalence of autosomal trisomy, it can be estimated that at least 3 foals per 10,000 live births are likely to have autosomal trisomy. Though, given that only 74 (i.e., 0.004%) of horses were genotyped within a month of birth, this is likely an underestimate. The economic consequence of undiagnosed trisomy in high-value breeding horses that are potentially infertile could be substantial. As horse genotyping for parentage verification and discovery is transitioning to medium-density single nucleotide polymorphism panels, routine genomic screening for autosomal aneuploidy could be readily undertaken and potentially should form a standard screening prerequisite along with other genetic defects at horse sales. Currently, thoroughbred horses registered for racing are not genotyped, and only a limited number of sport horse studbooks are using SNP genotyping. This highlights an opportunity for those already genotyping to expand their support for breeders through low-cost, high-value chromosomal screening at the time of registration rather than incurring additional costs over the horse’s life cycle to determine the root cause of certain phenotypes owing to the undiagnosed trisomy. Full article

Background: Food neophobia, defined as reluctance to try new foods, may lead to nutritional deficiencies and complicate dietary management—especially in individuals with Down syndrome, who often present with oral-motor dysfunction. This condition may result in nutritional deficiencies and difficulties in adhering to dietary recommendations, particularly in individuals with comorbidities. In individuals with Down syndrome (DS), who frequently present with oral motor disorders and chronic diseases, the problem may be especially pronounced. Objectives: The aim of the study was to assess the risk of food neophobia and feeding difficulties in children, adolescents, and young adults with Down syndrome, as well as their associations with age, gender, and body weight. Methods: The research was conducted using the CAWI method among 310 caregivers of individuals with DS in Poland. Two validated tools were employed: the Montreal Children’s Hospital Feeding Scale (MCH-FS) and the Food Neophobia Scale for Children (FNSC). Body mass index (BMI), comorbidities, and demographic data were also analyzed. Results: Findings revealed that the majority of participants (55.2%) had normal body weight, while 19.4% were undernourished and 6.5% were classified as obese. Feeding difficulties of moderate to very high severity were reported in 26.5% of the participants. A high risk of food neophobia was identified in 41.3% of respondents, most frequently in the preschool age group. A statistically significant association was observed between age and the severity of both feeding difficulties and neophobia (p < 0.05). However, no significant relationships were found with gender or body weight. Conclusions: Feeding difficulties and food neophobia are prevalent among individuals with Down syndrome, particularly in preschool-aged children. The findings highlight the necessity of an interdisciplinary therapeutic approach and the individualization of dietary interventions, taking developmental age into account. Further studies are warranted, with consideration of environmental and psychosocial factors. Full article

Chromosomal defects are a significant cause of perinatal death and childhood disability, occurring in 3.6–6.0 per 1000 births in unscreened populations. Common chromosomal defects include trisomy 21, 18, and 13, triploidy, and sex chromosome abnormalities. Screening for these defects began in the mid-1960s with the advent of amniocentesis, and various methods have since been developed to improve screening performance. Initial screening was based solely on maternal and gestational age, a method incorporated later into all subsequent screening methods giving an a priori background risk. This a priori background risk, which is further refined by maternal serum biochemistry, results of ultrasound examinations, and most recently, results of non-invasive prenatal testing by cell-free DNA in maternal blood. This paper will describe methods of screening for all chromosomal defects and their performance. Unlike most reviews, this paper covers not only screening tests for Down syndrome, but also screening methods for the other most common and less common chromosomal defects. Full article

Introduction: Chromosomal study via karyotype is one of the historical gold-standard procedures used to provide a clearer view of chromosomal trisomy abnormalities. It has been used to correlate several phenotypic manifestations that require immediate medical intervention. However, the laboratory procedure persisted with various drawbacks. The recent machine learning model shed light on prediction capabilities in the medical field. In this study, we aimed to use a support vector machine model for predicting postnatal chromosomal trisomy cases. Methods: A dataset of 946 neonatal records from the Royal Hospital, Muscat, Oman, covering the period from 2013 to 2023, has been used in this model. The model is based on features such as thyroxine hormone levels and thyroid-stimulating hormone levels. With different R packages, we used a support vector machine model with leave-one-out cross-validation and ten iterations to test three kernel functions: linear, radial, and polynomial. Results: Among the obtained kernel performances, the linear kernel has optimal classification performance. The training accuracy was 81%, and the testing accuracy was 82%. Sensitivity ranged from 97 to 98%, and specificity ranged from 79 to 80%. The area under the curve in relation to the training dataset came to 0.89, and it came to 0.90 for the test dataset. We deployed the trained models in a website tool called ChromoCheck. Conclusions: Our study is an example of how machine learning can be instrumental in augmenting conventional methods of cytogenetics diagnosis and decision-making in a clinical setup. Full article

Background/Objectives: The evaluation of metabolic and physiological health indicators in people with Down syndrome (DS) is crucial, since these people are more prone to metabolic problems. However, there is limited scientific evidence regarding the health status and health literacy (HL) of adults with DS and their legal guardians. This study aimed to assess the health status of adults with DS and determine the HL levels of their legal guardians. Methods: Eighteen adults (11 females, 7 males) with DS aged 28.64 ± 9.01 years were tested for health status, and their legal guardians completed the HL survey. Gender differences in all study variables were checked by t-tests for independent samples and Cohen’s D effect sizes (ESs). Differences in all study variables between parents with low and adequate HL were calculated via receiver operating characteristic curves. Results: Males were overweight, whereas females were obese (mean BMI = 26.51 and 30.10 for males and females, respectively). Females had higher high-density lipoprotein concentrations (large ES), whereas males had higher hematocrit and hemoglobin concentrations (large ES). Hematological parameters were the most significant variables that differed between parents with limited and adequate HL status (AUC = 0.79–0.87). Conclusions: These findings suggest that in the absence of severe comorbidities, adults with DS may achieve stable health profiles, particularly when supported by structured physical activity and informed caregiving. The influence of parental HL on health parameters points to the potential for parent-targeted health education to improve health outcomes and promote autonomy in individuals with DS through supported decision-making. Thus, our findings highlight the need for greater investment in caregiver and parental health education and systemic support to optimize health outcomes in adults with DS. Future research should explore interventions aimed at improving parental HL and examine the extent to which these efforts translate into improved health outcomes for people with DS. Full article

Down Syndrome or Trisomy 21 (T21) is a complex genetic disease characterized by the presence of an extra chromosome 21, which leads to multiple clinical features and manifestations that severely affect the patient’s quality of life. Various methods of prenatal screening have been developed over time, allowing informed decision-making. However, a common drawback of the current methods for detecting T21 is their invasive nature. Over the past years, mass-spectrometry-based omics technologies have become a key tool for discovering biomarkers for the prenatal screening of T21, particularly focusing on proteins, peptide sequences, or metabolites in samples, like amniotic fluid, umbilical cord blood, and others. Recently, there has been a noticeable shift towards using less invasive biological sample types (e.g., maternal serum, plasma, and urine) reflecting a growing interest in non-invasive methods for prenatal screening. These advances aim to improve the sensitivity and accuracy for T21 detection while reducing the risks associated with more invasive procedures. The first section of this paper offers an in-depth review of studies utilizing mass-spectrometry-based omics for the prenatal screening of T21. This part provides an overview of the methodologies employed and their key findings. Instead, the subsequent section offers a comprehensive examination of the differentially expressed proteins (DEPs) and metabolites (DEMs) reported in the literature in T21 prenatal screening. Additionally, pathway analysis is carried out to explore the biological pathways that these molecules are involved in and how they relate to the clinical features of the syndrome. These findings aim to guide future research in the field and foster the development of more advanced, less invasive prenatal screening techniques for T21. Full article

Background/Objectives: Down syndrome (DS) is the most common chromosomal abnormality in live births in the United States. Children with DS often require anesthesia for surgery or diagnostic imaging in their lives. These children present a unique perioperative risk profile due to a combination of anatomic and physiological alterations, along with associated comorbid conditions. There are limited studies on the perioperative outcomes of children with DS. This retrospective study assesses perioperative complications in pediatric patients with DS undergoing non-cardiac surgery or diagnostic imaging under anesthesia at a single tertiary pediatric hospital. Methods: The electronic medical record at a tertiary pediatric hospital was queried for children with DS who received anesthesia for non-cardiac surgery or diagnostic imaging from May 2016 to April 2021. The primary outcomes were complications defined as readmission, reoperation, or unexpected respiratory, cardiovascular, neurologic, surgical, or gastrointestinal issues. Exclusion criteria were cardiac surgery, age > 18 years, and records with incomplete or missing data. Results: A total of 1713 anesthetic records from 711 unique patients over five years were included in the final analysis. The study found a low overall complication rate (2.98%), with respiratory events being the most common (43.1%). While most complications are short term and resolved with treatment and time; there were also several severe, life-threatening complications. Increased procedural complexity, multiple procedures, and increased procedure duration were associated with higher complication rates, whereas patient age, sex, weight, and case urgency were not associated with higher complication rates. Conclusions: Children with DS often have comorbid conditions and require multiple life-improving surgeries. Our study found the perioperative complication rate for children with Down syndrome receiving anesthesia for non-cardiac surgery or diagnostic imaging is low, comparable to the general pediatric population. The findings indicate that anesthesia is well tolerated by children with DS. However, given patients’ unique anatomic and physiological differences, careful perioperative risk assessment and planning is essential. Clinical Implications: (a) What is already known about the topic: Pediatric patients with DS often require anesthesia for surgical procedures or medical imaging. They have anatomic and physiological alterations and comorbid conditions that may influence perioperative risk. (b) What new information this study adds: In a retrospective study at a tertiary pediatric hospital, patients with DS were found to have a low overall complication rate after anesthesia for non-cardiac surgery or diagnostic imaging. Increased procedural complexity, multiple procedures, and increased procedure duration were associated with higher complication rates. Full article

Background/Objectives: Non-invasive prenatal testing (NIPT) has become a widely used method for screening common fetal aneuploidies due to its high sensitivity and specificity compared to traditional screening methods. With various NIPT technologies available, such as whole-genome sequencing (WGS), single nucleotide polymorphisms (SNPs), microarray, and rolling circle amplification (RCA), understanding the accuracy and reliability of each method is critical for clinical decision-making. However, comprehensive evaluations comparing the performance of these NIPT methods, especially in terms of predictive values for trisomy detection, remain limited. A systematic review of the difference in accuracy of the different NIPT methods used for common aneuploidy screening. Methods: A systematic review of former clinical studies using different NIPT methods, such as whole-genome sequencing (WGS), a targeted method of single nucleotide polymorphisms (SNPs), microarray and rolling circle amplification (RCA). We collected data from the PubMed, Embase, Web of Science, Scopus, clinicaltrials.gov, and Cochrane library from the last 20 years, between 2003 January and 2023 October, without any language, search filter or publication type restrictions. Results: Two authors selected twenty articles including twenty-one studies to perform the systematic review. In these studies, altogether 92,164 pregnant women were tested by genomics-based non-invasive prenatal testing (NIPT). We extracted data on true positive, false positive, false negative, and true negative values from each study, and calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) from them. We collected data regarding trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13) detection from all studies. Conclusions: As a conclusion, for the detection of common fetal trisomies, different methods of NIPT perform similarly in terms of clinical sensitivity, specificity and NPV. However, the tests utilizing SNP and RCA had lower PPV values than other NIPT methods. Our research indicates all NIPT methods showed greater sensitivity for the detection of T21, above 97%, than traditional screening tests. For T18 detection, the targeted method with the microarray had a lower sensitivity compared to other tests. The SNP and the microarray-based test had high PPV, whilst the other tests, utilizing WGS, and the test with RCA had quite low PPV. Regarding T13 detection, all of the tests performed similarly in terms of clinical sensitivity, specificity, PPV, and NPV (with one exception—one of the tests using WGS had lower PPV). According to these results, there was no significant difference between the methods of NIPT, such as WGS, SNPs, microarray, and RCA, used to detect common trisomies, but the variation in PPV underlines the importance of invasive tests to derive positive NIPT results. We suggest that NIPT combined with US screening for structural abnormalities could further improve the utility of the non-invasive tests in pregnancy. This is the first independent systematic review into the efficacy of the different NIPT methods. Full article

Background/Objectives: Prevalence of umbilical cord cysts is largely unknown, mainly due to small dimensions and to the fact that only placental and fetal insertion of the umbilical cord are usually assessed. Older studies report a total prevalence of about 3%, regardless of the size. To date, no correlation between the gestational age, the size of the cyst at the moment of diagnosis and pregnancy prognosis can be made. Methods: We managed a case of a large umbilical cyst diagnosed in the first trimester. As our experience with this pathology was limited, we performed a systematic review in order to find out the optimal management. Results: We report a case of a large umbilical cord cyst that ended in fetal demise at 13 weeks in the absence of any chromosomal and structural anomalies. Our results differ from what was expected from our literature review. Sixteen papers were included in our analysis. According to the selected papers, single cysts are more frequent than multiple cysts (79% single cysts). The mean value of the maximum diameter of the cyst was 32 mm, and there was no difference in number considering the localization of the cyst. Considering the cases in which genetic testing was performed, there were 22.76% modified results. The most frequent genetic disorder was trisomy 18 (53.57% from the modified results). Conclusions: Large umbilical cord cysts are correlated with uncertain prognosis. We made the conclusion that large umbilical cord cystic lesions might have an unfavorable prognosis. Although there are case series that have shown an unproblematic evolution of the pregnancy, large umbilical cysts could be associated with increased risk of fetal anomalies and intrauterine fetal death. Full article

Background: Uniparental disomy (UPD) is the inheritance of both copies of a chromosome from a single parent, leading to distinct genetic conditions. Maternal UPD of chromosome 6 (UPD(6)mat) is extremely rare, with few molecularly confirmed cases reported. Methods: We report a prematurely born female with isodisomic UPD(6)mat, presenting with intrauterine growth restriction (IUGR), developmental delay, autism spectrum disorder, dysmorphic features, and a sacrococcygeal teratoma. In addition, we reviewed 24 confirmed UPD(6)mat cases to assess clinical patterns in prenatal findings, birth outcomes, and postnatal features. Results: Trio whole-exome sequencing revealed complete isodisomy of chromosome 6 and a de novo heterozygous DIAPH2 variant of uncertain significance. In the literature review, IUGR was present in 87% of cases, with most individuals born small for gestational age and preterm. Failure to thrive and neurodevelopmental issues were also frequent. While the exact molecular basis remains unknown, imprinting disturbances—similar to those in UPD(6)pat—and cryptic trisomy 6 mosaicism, particularly in heterodisomy, are the most likely mechanisms. No specific gene or consistent epigenetic abnormality has been identified. Conclusions: This study aims to enhance the understanding of the genetic and phenotypic spectrum of UPD(6)mat, improving diagnostic and management approaches for this ultra-rare genetic disorder. We propose a detailed list of clinical assessments and tests to be performed following the detection of maternal uniparental disomy of chromosome 6. Full article

Background/Objectives: Atlantoaxial instability (AAI) affects approximately 20% of individuals with Trisomy 21. Radiological screening has been debated for decades due to its unclear clinical utility and lack of standardized diagnostic criteria. This systematic review evaluates the indications, efficacy, and clinical implications of radiological screening for AAI in children with Trisomy 21. Methods: Following the PRISMA guidelines, we conducted a systematic search in PubMed, Embase, and Google Scholar for studies published between 1990 and May 2024. Studies were included if they assessed AAI screening in pediatric Trisomy 21 populations, defined AAI radiologically, and reported at least two cases. We extracted the demographic data, study design, radiological criteria, screening recommendations, and biases from these studies. Results: Of the 537 identified studies, 8 met the inclusion criteria, encompassing 2536 children (mean age: 7 years). Five studies supported routine screening, while three opposed it. Studies varied significantly in their AAI definitions, using atlanto-dental interval (ADI) thresholds of 4 mm to 6 mm, the space available for cord (SAC), and the basion-axial interval (BAI). No study demonstrated a definitive correlation between radiological findings and neurological symptoms. Conclusions: Routine radiological screening for AAI in asymptomatic children with Trisomy 21 is not supported by consistent evidence. A selective screening approach, focusing on symptomatic patients or those engaging in high-risk activities, may be more appropriate. The standardization of radiological criteria and prospective studies are needed to refine screening recommendations. Full article