Multiple Aneuploidy: First Report of a Patient Presenting with a Karyotype 45,X/48,XXX,+21.

INTRODUCTION: The dual diagnosis of Down syndrome and Turner syndrome in the same patient was clinically identified in the early 1950s before the development of karyotyping techniques. After that, several authors reported anecdotal patients and/or reviewed series of Down-Turner double aneuploidies due to a regular 46,X,+21 constitution or different combinations of abnormal cell lines. In such cases, the most typical presentation encompasses the female sex, Down syndrome phenotype, and chromosomal mosaicism. CASE PRESENTATION: Here we report a female patient presenting with short stature, dysmorphic features, developmental delay, and learning disabilities, whose karyotype revealed a previously undescribed 45,X[47]/48,XXX,+21[3] constitution. CONCLUSION: This is the first case encompassing these three aneuploidies together and, contrary to most previous reports, exhibiting a predominantly Turner syndrome phenotype associated with developmental delay.

MTHFR 677C>T and 1298A>C Variants in Mothers of Infants with Down Syndrome from Western Mexico.

Background: Several studies in mothers of infants with Down syndrome (DS) (MoIDS) have suggested that the 677C>T and 1298A>C variants of the 5,10-methylentetrahydrofolate reductase (MTHFR) gene can increase the risk of having a child with DS. Aim: This study aimed to evaluate the MTHFR 677C>T and 1298A>C variants as potential maternal risk factors for DS. Materials and Methods: Using TaqMan allelic discrimination assay, we genotyped 95 MoIDS and 164 control mothers from western Mexico. Data were analyzed using logistic regression analysis. Results: We found that MoIDS had a significantly higher risk for the MTHFR 677TT genotype (adjusted odds ratio [aOR] = 3.4, 95% confidence interval [95% CI]: 1.1-10.6), and the MTHFR 677T allele (aOR = 1.5, 95% CI: 1.0-2.3), particularly in MoIDS <35 years of age. Conclusions: Our findings indicate that the presence of the 677TT genotype and 677T allele of the MTHFR 677C>T variant are maternal risk factors for DS in Mexican MoIDS.

Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome.

BACKGROUND: Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates the underlying function of MX1, an effector gene of I-IFN, in DS-associated transcriptional regulation and phenotypic modulation. METHODS: We performed assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq) to explore the difference of chromatin accessibility between DS derived amniocytes (DSACs) and controls. We then combined the annotated differentially expressed genes (DEGs) and enriched transcriptional factors (TFs) targeting the promoter region from ATAC-seq results with the DEGs in RNA-seq, to identify key genes and pathways involved in alterations of biological processes and pathways in DS. RESULTS: Binding motif analysis showed a significant increase in chromatin accessibility of genes related to neural cell function, among others, in DSACs, which is primarily regulated by members of the activator protein-1 (AP-1) transcriptional factor family. Further studies indicated that MX Dynamin Like GTPase 1 (MX1), defined as one of the key effector genes of I-IFN, is a critical upstream regulator. Its overexpression induced expression of AP-1 TFs and mediated inflammatory response, thus leading to decreased cellular viability of DS cells. Moreover, treatment with specific AP-1 inhibitor T-5224 improved DS-associated phenotypes in DSACs. CONCLUSIONS: This study demonstrates that MX1-mediated AP-1 activation is partially responsible for cellular dysfunction of DS. T-5224 effectively ameliorated DS-associated phenotypes in DSACs, suggesting it as a potential treatment option for DS patients.

[Risk factors in the origin of Down syndrome]. / Factores de riesgo en el origen del síndrome de Down.

Down syndrome (DS) is the most common autosomal aneuploidy and the leading cause of intellectual disability of genetic origin worldwide. It is identified as a syndrome in which the variability of its clinical manifestations and the severity of its phenotype have a multifactorial origin. Worldwide prevalence ranges between 1 per 700 live births and several factors that may be involved in the origin of DS have been proposed. Our objective was to describe updates regarding risk factors in the cytogenetic origin or cause of DS. We conducted a narrative review study in which a literature search was carried out from January to June 2022 in databases such as PubMed, EBSCO, Medigraphic, ClinicalKey, and meta-search engines such as Elsevier and Evidence Alerts. Only articles published in the last 10 years in English and Spanish were included. The search terms used were: Down syndrome, risk factors, prevention. Although DS is a very common chromosomal pathology worldwide, there is no single risk factor at the origin of meiotic or mitotic nondisjunction of chromosome 21, but rather each of the associated risk factors contributes to a greater or lesser degree to a cytogenetic predisposition in the etiology of trisomy 21. During the review it was identified that the main established risk factor associated with DS is still advanced maternal age (≥ 35 years).

El síndrome de Down (SD) es la aneuploidía de autosomas más frecuente y la primera causa de discapacidad intelectual de origen genético a nivel mundial. Se identifica como una condición de vida en la que la variabilidad de sus manifestaciones clínicas y la gravedad del fenotipo tienen un origen multifactorial. La prevalencia mundial oscila entre 1 por cada 700 nacidos vivos y se han propuesto diversos factores de riesgo que pueden estar implicados en el origen del SD. Nuestro objetivo fue describir las actualizaciones con respecto a los factores de riesgo en el origen o causa citogenética del SD. Se realizó una revisión narrativa en la cual se condujo una búsqueda bibliográfica en el periodo de enero a junio de 2022 en bases de datos como PubMed, EBSCO, Medigraphic, ClinicalKey y metabuscadores como Elsevier y Evidence Alerts. Se incluyeron únicamente artículos publicados en los últimos 10 años en idioma inglés y español. Los términos de búsqueda utilizados fueron: Down syndrome, risk factors, prevention. Aunque el SD es una patología cromosómica muy frecuente a nivel internacional, no existe un factor de riesgo único en el origen de la no disyunción meiótica o mitótica del cromosoma 21, sino que cada uno de los factores de riesgo asociados contribuye en mayor o menor medida a una predisposición citogenética en la etiología de la trisomía 21. Durante la revisión se identificó que el principal factor de riesgo establecido asociado a SD sigue siendo la edad materna avanzada (≥ 35 años).

Association of C677T and A1298C polymorphisms of the MTHFR gene with maternal risk for Down syndrome: A meta-analysis of case-control studies.

BACKGROUND: Several studies around the world support the hypothesis that genetic polymorphisms involved in folate metabolism could be related to the maternal risk for Down syndrome (DS). Most of them investigated the role of MTHFR C677T and/or A1298C polymorphisms as maternal risk factors for DS, but their results are often conflicting and still inconclusive. METHODS: We conducted a systematic review and meta-analysis to clarify the association of MTHFR C677T and/or A1298C polymorphisms with the maternal risk of DS. Our search strategy selected 42 eligible case control studies for a total of 4131 case mothers and 5452 control mothers. The Newcastle-Ottawa Scale was used to assess the methodological quality of the selected studies. To assess the confidence of statistically significant associations we applied false positive report probability test, and we performed the trial sequential analysis to minimize the type I error and random error. RESULTS: We observed significant associations between the MTHFR C677T polymorphism and maternal risk for DS for each of the genetic models investigated (dominant, recessive, codominant, and allelic contrast). Subgroup analysis by region revelated significant association in the Asian population for all the genetic models investigated. Significant associations were also found for certain genetic models in North American, South American, and Middle Eastern populations, while no association was observed in Europeans. The MTHFR A1298C polymorphism did not show any association with the maternal risk of DS, either alone or in combination with the C677T one. The results of false positive report probability to verify the confidence of a significant association suggest that the association between the MTHFR C677T polymorphism and the maternal risk for DS is noteworthy, with high confidence in Asians. CONCLUSION: The results of this meta-analysis support that the MTHFR C677T polymorphism, but not the A1298C one, is associated with the maternal risk for DS. Further studies are required to better characterize the contribution of gene-gene and gene-nutrient interactions as well as those of other regional or ethnic factors that could explain the observed different effect size in different populations.

Circulating MicroRNAs in the Screening of Prenatal Down Syndrome.

OBJECTIVE: Screening tests are recommended to identify genetic defects, chromosomal aneuploidies, and structural birth defects. Sonographic and maternal serum-based options are available for the risk assessment of aneuploidy in the first and/or second trimester. Also, invasive diagnostic methods, such as amniocentesis, are used for prenatal diagnosis, but these methods carry a tangible risk to the fetus. However, in recent years, circulating fetal nucleic acids have a promising moleculer tool in the noninvasive prenatal diagnosis of fetal chromosomal aneuploidies. In this study, we aimed to explore the usability of microRNAs (miRNAs) in this process of prenatal diagnosis. METHODS: Fourteen pregnant patients who were found to be carrying fetuses with congenital anomalies were designated as the patient group; 16 pregnant women identified as being at risk of carrying children with such anomalies-but whose fetuses were later found to be anomaly-free-were assigned to control group 1; and 13 pregnant women who had been screened and who had not been identified as being at risk made up control group 2. An analysis of miRNA expression, isolated from maternal plasma and amniotic fluid samples, was performed by quantitative real-time polymerase chain reaction. RESULTS: It was found that hsa-miR-629-5p, hsa-miR-320c, hsa-miR-21-5p, hsa-let-7c-5p, hsa-miR-98-5p, hsa-miR-486-5p, hsa-miR-4732-5p, and hsa-miR-181a-5p levels increased in the patient group's maternal plasma compared to that of the control group. CONCLUSION: In light of these data, we believe that miRNAs may have an important role in the noninvasive prenatal diagnosis of fetal birth defects, especially Down syndrome.

Pharmacological Inhibition of p-21 Activated Kinase (PAK) Restores Impaired Neurite Outgrowth and Remodeling in a Cellular Model of Down Syndrome.

Down syndrome (DS) is characterized by the trisomy of chromosome 21 and by cognitive deficits that have been related to neuronal morphological alterations in humans, as well as in animal models. The gene encoding for amyloid precursor protein (APP) is present in autosome 21, and its overexpression in DS has been linked to neuronal dysfunction, cognitive deficit, and Alzheimer's disease-like dementia. In particular, the neuronal ability to extend processes and branching is affected. Current evidence suggests that APP could also regulate neurite growth through its role in the actin cytoskeleton, in part by influencing p21-activated kinase (PAK) activity. The latter effect is carried out by an increased abundance of the caspase cleavage-released carboxy-terminal C31 fragment. In this work, using a neuronal cell line named CTb, which derived from the cerebral cortex of a trisomy 16 mouse, an animal model of human DS, we observed an overexpression of APP, elevated caspase activity, augmented cleavage of the C-terminal fragment of APP, and increased PAK1 phosphorylation. Morphometric analyses showed that inhibition of PAK1 activity with FRAX486 increased the average length of the neurites, the number of crossings per Sholl ring, the formation of new processes, and stimulated the loss of processes. Considering our results, we propose that PAK hyperphosphorylation impairs neurite outgrowth and remodeling in the cellular model of DS, and therefore we suggest that PAK1 may be a potential pharmacological target.

Generation of Urine-Derived Induced Pluripotent Stem Cells and Cerebral Organoids for Modeling Down Syndrome.

Down syndrome (DS, or trisomy 21, T21), is the most common genetic cause of intellectual disability. Alterations in the complex process of cerebral cortex development contribute to the neurological deficits in DS, although the underlying molecular and cellular mechanisms are not completely understood. Human cerebral organoids (COs) derived from three-dimensional (3D) cultures of induced pluripotent stem cells (iPSCs) provide a new avenue for gaining a better understanding of DS neuropathology. In this study, we aimed to generate iPSCs from individuals with DS (T21-iPSCs) and euploid controls using urine-derived cells, which can be easily and noninvasively obtained from most individuals, and examine their ability to differentiate into neurons and astrocytes grown in monolayer cultures, as well as into 3D COs. We employed nonintegrating episomal vectors to generate urine-derived iPSC lines, and a simple-to-use system to produce COs with forebrain identity. We observed that both T21 and control urine-derived iPSC lines successfully differentiate into neurons and astrocytes in monolayer, as well as into COs that recapitulate early features of human cortical development, including organization of neural progenitor zones, programmed differentiation of excitatory and inhibitory neurons, and upper-and deep-layer cortical neurons as well as astrocytes. Our findings demonstrate for the first time the suitability of using urine-derived iPSC lines to produce COs for modeling DS.

Turner syndrome associated with Down syndrome: about a case / Síndrome Turner asociado a síndrome Down: a propósito de un caso

The coexistence of double aneuploidy of Down and Turner syndromes is rare; most cases have been due to double mitotic errors. The objective of the study was to report a case with monosomy of the X chromosome and trisomy of chromosome 21, in mosaic variety, highlighting the phenotypic effect that the presence of different chromosomal abnormalities can produce and compare with those reported in the literature. A 10-year-old Ecuadorian female, born to a multipregnant mother with 46 years at conception, is seen in consultation with a predominant clinical phenotype of Down syndrome, associated with menarche, presence of pubic and axillary villu, where a karyotype is verified 45 X[7]/47XX+ 21 [3]/46, X, der (X)(: p11.1-> q11.1)[1]/46,XX [1]. The present case is a double Turner-Down aneuploidy, with predominantly X monosomy cell line, who shows important mental retardation and some signs of puberal development not usually in Turner syndrome. These features highlight the clinical importance of doing a karyotype in mental retardation cases and searching low mosaics of another aneuploidies in atypical cases. Its complex chromosomal formula and support with molecular cytogenetics allowed diagnostic confirmation and genetic counseling.

La coexistencia de doble aneuploidía de los síndromes de Down y Turner es rara; la mayoría de los casos se han debido a dobles errores mitóticos. Reportar un caso con trisomía del cromosoma 21 y monosomía del cromosoma en X, en variedad mosaico, que curiosamente presenta un despertar puberal precoz y comparar con los reportados en la literatura. Paciente ecuatoriana de sexo femenino, de 10 años de edad, nacida de madre multigesta con 46 años a la concepción, que es vista en consulta con fenotipo clínico predominante de Síndrome Down, asociado a menarquia y telarquia, donde se constata un cariotipo. El presente caso es el primero informado de mosaicismo de doble aneuploidía de Turner-Down asociado con un despertar puberal precoz. Su fórmula cromosómica compleja y el apoyo con la citogenética molecular permitió la confirmación diagnostica y la asesoría genética.

Características ecográficas y anomalías congénitas en fetos con síndrome de Down / Ultrasound features and congenital anomalies in fetuses with Down syndrome

Resumen Objetivo: Describir y analizar los hallazgos ecográficos en 97 fetos portadores de síndrome de Down (SD) confirmado. Método: Se incluyeron todas las gestantes con diagnóstico prenatal de SD de nuestro centro, realizado por cariograma o reacción en cadena de la polimerasa cuantitativa fluorescente para aneuploidía. Se analizaron los informes genéticos y ecográficos, y se realizó un seguimiento posnatal. Resultados: De los 97 casos de SD, el 73% de los diagnósticos fueron entre las 11 y 14 semanas. El promedio de edad de las madres fue de 35,7 años. El 83% de los fetos con SD, evaluados a las 11-14 semanas, tuvieron una translucencia nucal ≥ 3,5 mm. Del total de los casos analizados, el 33% fueron portadores de una cardiopatía congénita, correspondiendo el 58% de estas a defectos mayores, principalmente anomalías del tabique auriculoventricular. Un 7,6% de los casos terminaron como mortinato, principalmente durante el tercer trimestre. Conclusiones: El ultrasonido es una herramienta muy sensible para la sospecha prenatal de SD y la detección de sus anomalías asociadas. Consideramos que la información aportada será útil para programar estrategias de pesquisa, organizar el control perinatal y precisar el consejo a los padres de fetos portadores de esta condición.

Abstract Objective: To describe and analyze the ultrasound findings in 97 fetuses with confirmed Down syndrome (DS). Method: All pregnant women with prenatal diagnosis of DS in our center, performed by karyotype or quantitative fluorescent polymerase chain reaction for aneuploidy, were included. Genetic and ultrasound reports were analyzed, as well as postnatal follow-up. Results: Of the 97 cases of DS, 73% of the diagnoses were between 11-14 weeks. The average age of the mothers was 35.7 years. 83% of our fetuses with DS, evaluated between 11-14 weeks, had a nuchal translucency ≥ 3.5 mm. Of the total of the fetuses analyzed, 33% were carriers of congenital heart disease, 58% of these correspond to a major defect, mainly anomalies of the atrioventricular septum. 7.6% of cases ended as stillbirth, mainly during the third trimester. Conclusions: Ultrasound is a very sensitive tool for prenatal suspicion of DS and the detection of its associated abnormalities. We believe that the information provided will be useful to program screening strategies, organize perinatal control and to counselling parents of fetuses carrying this condition.

A sensitive and inexpensive high-resolution melting-based testing algorithm for diagnosis of transient abnormal myelopoiesis and myeloid leukemia of Down syndrome.

Patients with Down syndrome (DS) are commonly affected by a pre-leukemic disorder known as transient abnormal myelopoiesis (TAM). This condition usually undergoes spontaneous remission within the first 2 months after birth; however, in children under 5, 20%-30% of cases evolve to myeloid leukemia of Down syndrome (ML-DS). TAM and ML-DS are caused by co-operation between trisomy 21 and acquired mutations in the GATA1 gene. Currently, only next-generation sequencing (NGS)-based methodologies are sufficiently sensitive for diagnosis in samples with small GATA1 mutant clones (≤10% blasts). Alternatively, this study presents research on a new, fast, sensitive, and inexpensive high-resolution melting (HRM)-based diagnostic approach that allows the detection of most cases of GATA1 mutations, including silent TAM. The algorithm first uses flow cytometry for blast count, followed by HRM and Sanger sequencing to search for mutations on exons 2 and 3 of GATA1. We analyzed 138 samples of DS patients: 110 of asymptomatic neonates, 10 suspected of having TAM, and 18 suspected of having ML-DS. Our algorithm enabled the identification of 33 mutant samples, among them five cases of silent TAM (5/110) and seven cases of ML-DS (7/18) with blast count ≤10%, in which GATA1 alterations were easily detected by HRM. Depending on the type of genetic variation and its location, our methodology reached sensitivity similar to that obtained by NGS (0.3%) at a considerably reduced time and cost, thus making it accessible worldwide.

Integrated Quantitative Neuro-Transcriptome Analysis of Several Brain Areas in Human Trisomy 21.

BACKGROUND: Although Down syndrome (DS) is the most frequent human chromosomal disorder and it causes mainly intellectual disability, its clinical presentation is complex and variable. OBJECTIVE: We aimed to analyze and compare the transcriptome disruption in several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond chromosome 21. METHODS: We used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of the human brain. We calculated the differential gene expression (Z-ratio) of all genes. RESULTS: We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16-22 weeks of gestation and 39-42 years (R2 = 0.06) and the highest Z-ratio correlation between the age ranks of 30-39 years and 40-42 years (R2 = 0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole. CONCLUSIONS: Our results support the hypothesis of a systemic imbalance of brain protein homeostasis, or proteostasis network of cognitive and neuroplasticity process, as new model to explain the important effect on the neurophenotype of trisomy that occur not only in the loci of chromosome 21 but also in genes located in other chromosomes.

Profiling of circulating chromosome 21-encoded microRNAs, miR-155, and let-7c, in down syndrome.

BACKGROUND: Down syndrome (DS) is the most common chromosomal survival aneuploidy. The increase in DS life expectancy further heightens the risk of dementia, principally early-onset Alzheimer's disease (AD). AD risk in DS is higher, considering that this population may also develop metabolic diseases such as obesity, dyslipidemias, and diabetes mellitus. The extra genetic material that characterizes DS causes an imbalance in the genetic dosage, including over-expression of AD's key pathophysiological molecules and the gene expression regulators, the microRNAs (miRNAs). Two miRNAs, chromosome 21-encoded, miR-155, and let-7c, are associated with cognitive impairment and dementia in adults; but, expression dynamics and relationship with clinical variables during the DS's lifespan had remained hitherto unexplored. METHODS: The anthropometric, clinical, biochemical, and profile expression of circulating miR-155 and let-7c were analyzed in a population of 52 control and 50 DS subjects divided into the young group (Aged ≤20 years) and the adult group (Aged ≥21 years). RESULTS: The expression changes for miR-155 were not significant; nevertheless, a negative correlation with HDL-Cholesterol concentrations was observed. Notably, let-7c was over-expressed in DS from young and old ages. CONCLUSION: Overall, our results suggest that let-7c plays a role from the early stages of DS's cognitive impairment while overexpression of miR-155 may be related to lipid metabolism changes. Further studies of both miRNAs will shed light on their potential as therapeutic targets to prevent or delay DS's cognitive impairment.

Cytogenetic Patterns, Congenital Heart Disease, and Thyroid Dysfunction in Children with Down Syndrome.

OBJECTIVES: To study the cytogenetic patterns, congenital heart disease, and thyroid dysfunction in children with Down syndrome. STUDY DESIGN: This was a retrospective observational study of children with Down syndrome over a period of 20 years, from a major referral institution in Kerala state, South India. The cytogenetic patterns, echocardiography reports, and thyroid profiles were analyzed using SPSS, version 20, software. The prevalence of heart disease and thyroid status in the various cytogenetic patterns also were analyzed. RESULTS: The prevalence of translocation (9.45%) was high compared with the reported 4% in the literature. More of the younger mothers had translocation with a greater, but not statically significant, incidence of heart disease. Mosaic karotypes (3.04%) were also greater than reported (1%) in the literature, with female preponderance. Heart disease was seen in 58% of cases, with atrial septal defect being the most common lesion, compared with atrioventricular septal defect noted in literature. Hypothyroidism was noted in 31.2% with no difference among the cytogenetic groups. There was no case of hyperthyroidism. CONCLUSIONS: The high prevalence of translocation and mosaic Down syndrome stresses the need for routine karyotyping in children with Down syndrome. The need for routine screening and regular follow up of heart diseases and thyroid status should be emphasized.

Aurora kinase genetic polymorphisms: an association study in Down syndrome and spontaneous abortion.

Aneuploidies, such as Down syndrome (DS), are the leading cause of pregnancy loss. Abnormalities in aurora kinase proteins result in genomic instability and aneuploidy, mainly in tumors. Thus, polymorphisms in Aurora kinase genes could influence the occurrence of DS and spontaneous abortion. A case-control study was conducted including 124 mothers of DS children (DSM) and 219 control mothers (CM) to investigate DS risk according to AURKA and AURKC polymorphisms. Genotyping was performed using TaqMan real-time PCR. The minor allele frequency (MAF) observed in AURKA rs2273535 was, respectively, 0.23 in DSM and 0.20 in CM, whereas the frequency of the AURKC rs758099 T allele was 0.32 in case and 0.33 in control mothers. Statistical analysis showed no significant difference in the distribution of genotypes and allele frequencies between DSM and CM. According to previous history of spontaneous abortion, the AURKA rs2273535 genotypes (TT + AT vs. AA: OR 2.54, 95% CI 1.13-5.71, p = 0.02; AT vs. AA: OR 2.39, 95% CI 1.03-5.51, p = 0.04; T vs. A: OR 2.08, 95% CI 1.12-3.90, p = 0.02) and AURKC rs758099 (TT vs. CC: OR 4.34, 95% CI 1.03-18.02, p = 0.04; TT + CT vs. CC: OR 2.52, 95% CI 1.02-6.23, p = 0.04; T vs. C: OR 2.03, 95% CI 1.09-3.80, p = 0.02) were observed as risk factors for spontaneous abortion in case mothers. Our study suggests a possible relationship between AURKA/AURKC variants and increased risk of spontaneous abortion within Down syndrome mothers.

Differential microRNA expression profile in blood of children with Down syndrome suggests a role in immunological dysfunction.

Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), results in a broad range of phenotypes. However, the determinants contributing to the complex and variable phenotypic expression of DS are still not fully known. Changes in microRNAs (miRNAs), short non-coding RNA molecules that regulate gene expression post-transcriptionally, have been associated with some DS phenotypes. Here, we investigated the genome-wide mature miRNA expression profile in peripheral blood mononuclear cells (PBMCs) of children with DS and controls and identified biological processes and pathways relevant to the DS pathogenesis. The expression of 754 mature miRNAs was profiled in PBMCs from six children with DS and six controls by RT-qPCR using TaqMan® Array Human MicroRNA Cards. Functions and signaling pathways analyses were performed using DIANA-miRPath v.3 and DIANA-microT-CDS software. Children with DS presented six differentially expressed miRNAs (DEmiRs): four overexpressed (miR-378a-3p, miR-130b-5p, miR-942-5p, and miR-424-3p) and two downregulated (miR-452-5p and miR-668-3p). HSA21-derived miRNAs investigated were not found to be differentially expressed between the groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed potential target genes involved in biological processes and pathways pertinent to immune response, e.g., toll-like receptors (TLRs) signaling, Hippo, and transforming growth factor ß (TGF-ß) signaling pathways. These results suggest that altered miRNA expression could be contributing to the well-known immunological dysfunction observed in individuals with DS.

Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome: A protocol for systematic review and/or meta-analysis.

BACKGROUND: Down syndrome (DS) is one of the most common chromosomal abnormalities among live-born babies and one of the best-known intellectual disability disorders in humans. Errors leading to trisomy 21 are primarily arising from defects in chromosomal segregation during maternal meiosis (about 88% of cases), and the focus of many investigations has been to identify maternal risk factors favoring chromosome 21 malsegregation during oogenesis. Maternal polymorphisms of genes required for folate metabolism are the most investigated risk factors for the birth of children with DS. Through this review, we sought to investigate the association of the polymorphisms "C677T" and "A1298C" of the MTHFR gene with maternal risk for DS. METHODS: We will use the databases PubMed, Embase, Scopus and Web of Science to search for case-control studies published from 1999 up to September 2021 without language restriction. Results will be presented as relative risks and 95% confidence intervals for dichotomous outcomes and mean differences, or standardized mean differences along with 95% confidence intervals, for continuous outcomes. The all data synthesis will be analyzed on the Review Manager 5.2 version software. RESULTS: This study will be able to clarify all the doubts we seek and that it will be able to provide accurate data that will be able to describe how these polymorphisms can act to increase the predisposition for the birth of children with DS in different populations and under different dietary conditions. CONCLUSIONS: This study will clarify the relationship between C677T and A1298C polymorphisms MTHFR gene with increased the maternal risk for Down syndrome. REGISTRATION: This systematic review and meta-analysis protocol has been registered on the Prospective Registry of International Systematic Review and Meta-analyses: CRD42021269338.

Prenatal cytogenetic diagnosis: results obtained in the specialized laboratory of Clínica Universitaria Colombia from 2013 to 2019.

OBJECTIVE: Prenatal cytogenetic evaluation is a key tool for identifying alterations in pregnant women with high risk for fetal chromosomal abnormalities (CA). In Colombia, there are not large-scale reports about the prevalence and pattern of CA in prenatal cytogenetic analysis. METHOD: A descriptive study was performed from registers of prenatal cytogenetic analysis on amniotic fluid (AF), chorionic villus biopsy (CVS), and fetal blood (FB) samples sent to the specialized laboratory of the Clínica Universitaria Colombia between 2013 and 2019. RESULTS: The prevalence of CA was 20.9%. The trisomies 21, 18, 13, and monosomy X were the most frequent aneuploidies, and the derivative chromosomes were the most frequent structural abnormalities. Although the rate of CA was higher in women over the age of 35 years old; monosomy X, unbalanced rearrangements, and microduplications were associated with the group of women under the age of 35 (p < .05). Trisomies 21 and 18 were the most common aneuploidies identified by FISH and were found to be altered in 52% of the aCGH studies. Ultrasonographic markers associated with CA were the most frequent clinical indication. CONCLUSION: In Colombia, the invasive prenatal cytogenetic analysis continues being an important diagnostic tool available for pregnant women with high risk for fetal CA.

Screening of six polymorphisms related with folate metabolism in parents of individuals with Down syndrome.

OBJECTIVE: The study aim to investigate MTHFR C677T, MTHFR A1298C, RFC1 A80G, MTR A2756G, CBS 844ins68, MTRR A66G polymorphisms in Down syndrome (DS) parents. METHODS: Polymorphisms were evaluated in 35 mothers and 24 fathers of individuals with free trisomy of chromosome 21 confirmed by karyotype. The control group included 26 mothers and 26 fathers who had no children with DS. The molecular analysis was performed by polymerase chain reaction and restriction fragment length polymorphism (reaction chain polymerase restriction fragment length polymorphism) or polymerase chain reaction. The χ2 test (chi-square) was used to compare allele's differences among the study and the control group. Hardy-Weinberg equilibrium model was performed by χ2 testing. Multiple logistic regression models and binary logistic regression used to determine the association between polymorphisms and parental DS risk. RESULTS: This study did not reveal any significant difference in frequencies of polymorphisms. The haplotype analysis did not reveal linkage disequilibrium. The logistic regression analysis did not demonstrate differences between the groups. However, the binary logistic regression showed a higher frequency of the polymorphic homozygote genotype in DS parent group to codominant and dominant model in the RFC1 A80G. CONCLUSION: In conclusion, although the screening results were significant only to the RFC1 A80G polymorphism, the other determinations of the genetic factors associated with abnormal chromosome segregation could be helpful in future studies, including other polymorphisms involved in folate metabolism.