Search Results (325)

Background: Oxidative stress is an important contributor to brain abnormalities in Down syndrome (DS), but the status of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway during early postnatal development remains poorly understood. The current study aimed to investigate whether an impairment of the NRF2 pathway is already present in the Ts65Dn mouse model of trisomy 21 at neonatal life stages and whether early treatment with astaxanthin-loaded stealth solid lipid nanoparticles (AST-SSLNs) positively impacts NRF2 signaling and reduces oxidative stress. Methods: Hippocampal NRF2 pathway components and oxidative stress markers were analyzed in neonate Ts65Dn and euploid mice. From postnatal day (P)3 to P15, mice received daily subcutaneous injections of AST-SSLNs or unloaded nanoparticles. NRF2 pathway activation, reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and safety parameters were evaluated. Results: Untreated Ts65Dn mice exhibited early impairment of the NRF2 pathway, characterized by increased BACH1, reduced NRF2 activation, and decreased HO-1 expression. Neonatal AST-SSLN treatment enhanced NRF2 activation, improved HO-1 levels, and normalized ROS accumulation, lipid peroxidation, and protein carbonylation in the hippocampus, a brain region critically impaired in DS. Treatment had no adverse effects on survival, body weight, or brain weight. Conclusions: These findings demonstrate that NRF2 pathway dysfunction is an early event in trisomy 21 and identify the neonatal period as a potential therapeutic window to counteract oxidative stress. AST-SSLNs represent a promising nanomedicine-based strategy to activate the impaired NRF2 pathway and reduce early hippocampal oxidative damage in DS. Full article

Mounting evidence implicates dysregulation of the neuroimmune system in Alzheimer’s disease (AD). Neuroimmune cells, namely microglia and astrocytes, have the potential to contribute to AD through mechanisms such as promoting neuroinflammation and propagating amyloid-β (Aβ) and tau aggregates. Human induced pluripotent stem cell (hiPSC)-derived models offer advantages for studying the AD neuroimmune system, such as recapitulating genetic variants associated with the disease and allowing for precise manipulation of human cells in vitro. Here, we provide an overview of modern techniques for generating 2-dimensional (2D) monocultures and co-cultures, 3-dimensional (3D) organoids and assembloids, and chimeras containing hiPSC-derived microglia and astrocytes. Then, we highlight recent studies that have utilized hiPSC-derived neuroimmune models to investigate AD risk variants in genes encoding apolipoprotein E (APOE) and triggering receptor on myeloid cells 2 (TREM2), mutations known to cause familial AD in genes encoding presenilin 1 (PSEN1) and 2 (PSEN2) and amyloid precursor protein (APP), and trisomy 21 leading to Down syndrome-associated AD (DS-AD). We then briefly summarize recent studies that have utilized hiPSC-derived neuroimmune models lacking disease-associated variants to study the clearance of Aβ and tau aggregates. Finally, we discuss notable limitations of these models and reflect on future directions for this area of research, including the use of cultures with increasing cellular diversity and structural complexity, advancements in live-imaging techniques for detecting AD pathology in vitro, and drug screening. Full article

Background/Objectives: Genomic sequencing can shorten the diagnostic pathway for selected symptomatic neonates and young infants, but evidence from such cohorts should not be extrapolated to population newborn screening. This study describes molecular findings and potential clinical implications in 25 unrelated patients younger than 6 months at referral with heterogeneous, predominantly neurological phenotypes and no established molecular diagnosis. Methods: The first 17 patients underwent whole-exome sequencing (WES), and the subsequent 8 underwent whole-genome sequencing (WGS) under sequential laboratory protocols; allocation was not randomized, and the study was not designed to compare platforms. Results: Pathogenic or likely pathogenic findings providing a definitive or likely molecular diagnosis were identified in 7/25 patients (28.0%; 95% confidence interval [CI], 14.3–47.6), including sequence variants, one 20q13.33 deletion, and mosaic trisomy 9. An additional RANBP2 variant was interpreted as a susceptibility-associated finding in a patient with infection-related encephalitis, yielding clinically relevant findings in 8/25 patients (32.0%; 95% CI, 17.2–51.6). Three definitive diagnoses involved disorders with established disease-specific management considerations; however, patient-level treatment changes, turnaround times, and outcomes were not systematically assessed. Conclusions: These findings support the diagnostic value of genomic testing in selected symptomatic neonates and young infants, while the small, heterogeneous cohort, sequential non-equivalent workflows, and incomplete outcome data preclude conclusions about comparative WES/WGS performance or population newborn screening. Full article

Background/Objectives: Prenatal chromosomal assessment can benefit from the complementary use of non-invasive prenatal testing (NIPT), chromosomal microarray analysis (CMA), and karyotyping because each test provides different information. Methods: We retrospectively analyzed 14,011 fetus-specific amniotic fluid cases obtained through second-trimester amniocentesis between 2014 and 2023. The study included overlapping subgroups tested by NIPT and karyotyping (n = 1300), CMA and karyotyping (n = 444), or all three methods (n = 78). Results: Karyotyping identified fetal chromosomal abnormalities in 1288 cases (9.2%). Among 983 evaluable cases in the clinically selected NIPT–karyotyping subgroup referred for invasive diagnosis by amniocentesis, the positive predictive value was 88.8% for trisomy 21, 66.7% for trisomy 18, 21.4% for trisomy 13, and 37.0% for sex chromosome abnormalities. Because these estimates were derived from a highly selected referral cohort rather than an unselected prenatal screening population, the PPV and NPV values should be interpreted within this referral setting and should not be generalized to unselected prenatal screening populations. Low-risk or inconclusive NIPT results did not completely exclude fetal chromosomal abnormalities. CMA detected pathogenic or likely pathogenic copy-number findings in 17 of 397 cases with normal karyotypes and provided additional molecular information in selected cases with abnormal karyotypes. Conversely, karyotyping identified 11 abnormalities among 388 cases with only likely benign, benign, or normal CMA results, including 10 apparently balanced reciprocal translocations and one diploid–tetraploid mosaicism. Conclusions: These findings show that NIPT, CMA, and karyotyping provide complementary rather than interchangeable information. High-risk NIPT results should be confirmed by invasive diagnostic testing, while CMA and karyotyping should be selected according to the clinical indication and suspected type of abnormality. Full article

Background/Objectives: Advanced maternal age (≥35 years) significantly increases the risk of fetal chromosomal abnormalities, particularly trisomies 21, 18, and 13. Non-invasive prenatal testing (NIPT) based on cell-free fetal DNA (cffDNA) in maternal plasma has substantially improved the accuracy and safety of prenatal screening. Methods: We previously developed and clinically validated a multiplex droplet digital PCR (ddPCR)-based NIPT assay for detecting fetal trisomies 21, 18, and 13 in Mongolia. The assay targeted specific loci on chromosomes 21, 18, and 13, using chromosome 1 as an internal reference. A Z-score threshold > 3 indicated high risk, and all positive results were confirmed by invasive karyotyping. Results: In this study, we collected 74 pregnant women of advanced maternal age and samples were successfully analyzed, with high technical performance (mean > 100,000 accepted droplets per reaction and clear signal separation). Ten high-risk pregnancy cases were identified (eight trisomy 21 and two trisomy 18), all of which showed complete concordance with confirmatory karyotyping. Complete concordance with available reference standard results were observed in this limited cohort. No trisomy 13 cases were detected. Conclusions: This ddPCR-based NIPT assay exhibited excellent diagnostic accuracy and reproducibility in a Mongolian cohort of advanced-maternal-age pregnancies. Its technical simplicity, relatively low cost, and minimal infrastructure requirements make it a promising tool for implementation in resource-limited settings. However, the small sample size limits generalizability, and larger multicenter studies are needed to confirm clinical utility across broader populations, including low-risk pregnancies. Full article

Short tandem repeat (STR) analysis is the main reference standard in forensic genetics. Despite its reliability, rare genetic anomalies like triallelic patterns and microvariants challenge profile interpretation. This study characterizes an exceptional genetic finding identified during routine casework at the Research Institute of Forensic Science in Sofia, Bulgaria. DNA was isolated from dental remains of an unidentified male corpse and amplified using the Investigator^® ESSplex SE Plus kit targeting 15 autosomal STR loci. A well-balanced male genotype was obtained across 14 loci; however, a rare triallelic anomaly emerged at D19S433 (19q12). Three distinct peaks were identified: standard alleles 13 and 14, and an off-ladder allele at 261.09 bp, designated as microvariant 15.3. Quantitative peak height analysis showed that the combined intensity of alleles 13 and 14 (~1316 RFU) was approximately equal to that of microvariant 15.3 (1054 RFU). This balance confirms a Type I triallelic configuration, indicative of a localized somatic mutation or segmental duplication rather than trisomy or DNA mixture. Global databases (NIST STRBase and STRidER) and regional Bulgarian data confirmed that this specific 13/14/15.3 combination has not been previously documented. Documenting rare STR variations is critical to enriching genomic databases and ensuring maximum accuracy in forensic interpretations. Full article

Background/Objectives: Absent or hypoplastic nasal bone is strongly associated with Trisomy 21 and other common aneuploidies. Nevertheless, there is a growing body of literature that has associated absence or hypoplasia of the nasal bone with underlying genetic aberrations, other than Trisomy 21. While karyotyping effectively identifies substantial structural mutations, it is limited by its inability to detect submicroscopic copy number variants, thereby constraining the identification of pathological submicroscopic DNA gains or losses. The main objective of our study was to conduct a systematic literature review and a meta-analysis to evaluate the incremental yield of chromosomal microarray analysis compared to karyotyping in cases of isolated absence/hypoplasia of the fetal nasal bone. Methods: Our review was designed according to the PRISMA guidelines. It included all observational studies that reported the results of CMA testing in fetuses diagnosed with absent or hypoplastic nasal bone without additional structural abnormalities or findings that would not qualify as structural abnormalities (soft signs) (isolated absent/hypoplastic nasal bone). Results: The study included 15 studies with a total of 1328 cases of affected fetuses that met the inclusion criteria for analysis. Combined data from these studies revealed an overall 3% incremental yield of CMA over karyotyping (95% CI 1–4%, I² = 62%) in isolated cases. Conclusions: Our findings may be beneficial in clinical practice to provide management strategies and counsel couples, personalizing, as such, patient care and assisting clinicians when encountering this prevalent clinical entity. Full article

Background: Trisomy 21 (T21) is strongly associated with congenital heart disease, particularly atrioventricular septal defect (AVSD), ventricular septal defect (VSD), atrial septal defect (ASD) and selected conotruncal and arch anomalies. First- and second-trimester ultrasound, Doppler and fetal cardiac MRI enable increasingly early and detailed characterization of these lesions, while advances in molecular cardiogenesis have linked specific phenotypes to dosage-sensitive genes on chromosome 21. Methods: This narrative review synthesizes contemporary evidence on structural and functional cardiovascular anomalies in T21 fetuses in the first and second trimester, integrating fetal echocardiography, Doppler assessment and fetal cardiac MRI with embryologic and molecular insights, and summarizing trimester-specific detectability and pathophysiologic links to candidate genes in the Down syndrome-critical region. Approximately one quarter to one third of T21 fetuses have major congenital heart disease on high-quality prenatal echocardiography, with AVSD representing about half of all lesions and VSD, tetralogy of Fallot (TOF), arch anomalies, venous return abnormalities and functional markers (increased nuchal translucency, tricuspid regurgitation, ductus venosus abnormalities) comprising the remainder. Results: First-trimester detection relies on functional markers and early four-chamber and outflow-tract views, whereas second-trimester studies refine anatomic definition and hemodynamics, with MRI reserved for complex cases. Overexpression of genes such as DSCAM, COL6A1/COL6A2, DYRK1A and RCAN1 perturbs endocardial cushion, conotruncal and vascular development. Conclusions: Early, protocol-driven cardiac imaging in T21 supports timely diagnosis, risk stratification and multidisciplinary counselling, and links fetal imaging phenotypes with chromosome 21 gene dosage to advance personalized management and future genotype–phenotype research. Full article

Down syndrome (DS), caused by trisomy 21, is associated with a wide spectrum of endocrine and gastrointestinal disorders that often arise early in life and significantly impact long-term health. This narrative review examines the pathophysiological mechanisms underlying these conditions, with a particular focus on their bidirectional interactions. Endocrine abnormalities in DS, including thyroid dysfunction, type 1 diabetes mellitus, growth impairment, and altered bone metabolism, occur at higher rates than in the general population and are largely driven by immune dysregulation, chronic inflammation, and gene dosage effects. Similarly, gastrointestinal disorders—ranging from congenital malformations to autoimmune conditions such as celiac disease—are highly prevalent and often present with atypical clinical features. Emerging evidence highlights the central role of gut dysbiosis, characterized by reduced microbial diversity and increased pro-inflammatory taxa, in modulating immune and metabolic pathways. This altered gut environment contributes to a chronic inflammatory state and may promote autoimmunity and endocrine dysfunction through the gut–endocrine–immune axis. Nutritional deficiencies and epigenetic factors, including microRNA dysregulation, further influence disease expression. Understanding this complex cross-talk is essential for improving clinical management. Integrated, multidisciplinary approaches and early screening strategies are crucial to optimize outcomes and guide future research in DS. Full article

Background: The fetal circulatory system is characterized by the presence of physiological vascular shunts—the ductus venosus, foramen ovale, and ductus arteriosus—which enable a significant portion of blood to bypass the pulmonary circulation and partially the hepatic portal system. This mechanism ensures preferential delivery of oxygenated blood to the brain, heart, and upper body. Agenesis of the ductus venosus (ADV) is a rare vascular anomaly associated with diverse anatomical variations and clinical outcomes. Objectives: This systematic review aimed to determine the prevalence of ADV and to assess the frequency of intrahepatic and extrahepatic types. Additional objectives were to identify the most common drainage sites of the umbilical vein (UV) in extrahepatic ADV, evaluate the genetic abnormalities, congenital heart defects, and extracardiac anomalies most frequently associated with ADV, and establish the prognosis of affected fetuses. Methods: A comprehensive literature search was conducted in the PubMed, Embase, and Web of Science databases using predefined and precise inclusion criteria. Results: The overall prevalence of ADV in the general population was 0.05%. The intrahepatic and extrahepatic types occurred with comparable frequencies, accounting for 51.2% and 48.8% of cases, respectively. In extrahepatic ADV, the most common drainage site of the UV was the right atrium (48%). The most frequent genetic abnormalities were trisomy 21 (12%) and Turner syndrome (6%). Among congenital heart defects, ventricular septal defect (22.7%) and atrioventricular septal defect (8.8%) were most prevalent. Functional consequences were observed in 37.4% of fetuses with isolated ADV, most commonly cardiomegaly. Conclusions: ADV is a rare fetal vascular anomaly. With the increasing availability and utilization of prenatal diagnostic techniques, expanding knowledge of this condition and its clinical implications is essential for accurate diagnosis, management, and prognostic assessment. Full article

Background/Objectives: Non-invasive prenatal testing (NIPT) for fetal aneuploidy requires accurate trisomy detection together with reliable fetal fraction assessment. This study evaluated the clinical feasibility of a 106-plex digital PCR (dPCR) NIPT assay for trisomies 13, 18, and 21 with internal fetal fraction quantification. Methods: We consecutively recruited 470 women with high-risk singleton pregnancies. Fetal trisomies were detected using dPCR-NIPT and confirmed by invasive prenatal diagnosis. Pregnancies with negative prenatal diagnostic results were followed to birth. Analytical performance and quality control were assessed using trisomic DNA. The euploid cut-off and diagnostic performance were evaluated in two independent maternal plasma sample sets, using invasive diagnosis and clinical outcome as the reference standard. Results: dPCR-NIPT measured fetal fraction irrespective of fetal sex and detected trisomies at fetal fractions ≥3% using 5 ng DNA. A total of 12 of 470 plasma samples failed cell-free DNA quality control and were excluded before dPCR testing. Of the remaining 458 samples, 5 had fetal fractions below 3% and were classified as failed tests, yielding a nonreportable rate of 1.1%. Using a cut-off of 6.9 established in 103 training samples, no false-positive or false-negative trisomy calls were observed in the 350-sample testing set, corresponding to 100% sensitivity (95% confidence interval [CI], 85.18–100%) and 100% specificity (95% CI, 98.88–100%) for 23 confirmed trisomies. Conclusions: This proof-of-principle study supports the feasibility of fetal fraction-informed dPCR-NIPT for trisomy detection in high-risk singleton pregnancies. Larger prospective studies in average-risk and earlier-gestation populations are required. Full article

The genomic landscape of myelodysplastic syndromes/neoplasms (MDS), a heterogeneous group of myeloid malignancies defined by bone marrow cell dysplasia with ineffective hematopoiesis, includes somatic and, less frequently, germline mutations in hematopoietic stem and progenitor cells, along with chromosomal abnormalities. The latest World Health Organization 2022 classification of myeloid neoplasms, as well as stratification in lower-risk (LR) and higher-risk (HR) MDS using either the Revised International Prognostic Scoring System (IPSS-R) or the Molecular International Prognostic Scoring System (IPSS-M), guide prognostic assessment and risk-adjusted therapy. We report the case of an 81-year-old patient diagnosed with LR-MDS according to IPSS-R that exhibited direct progression to acute myeloid leukemia. The retrospective analysis of paired DNA samples from MDS and leukemic phases, obtained four months apart, using both targeted next-generation sequencing and single nucleotide polymorphism array, indicated swift alterations in the genomic profile, being suggested that the leukemic clone emerged from the clone harboring homozygous TET2 and heterozygous SRSF2 variants that acquired RUNX1, BCOR, BCORL1 likely pathogenic mutations and trisomy 13. By employing IPSS-M for prognostic evaluation at the MDS phase, the patient would have been assigned to the HR-MDS category with a possible benefit from hypomethylating agent therapy. Risk stratification is of pivotal importance in a patient-centered approach to MDS treatment being significantly improved by incorporating the molecular genetic findings. Full article

Moyamoya angiopathy (MMA) is a rare, chronic progressive cerebrovascular condition characterized by bilateral stenosis or occlusion of the terminal internal carotid arteries and their major branches. This progressive occlusion triggers the development of telangiectatic and fragile vessels at the base of the brain, creating the characteristic angiographic appearance of a “puff of smoke.” Depending on the etiology, MMA is classified as Moyamoya Disease (MMD) when idiopathic and primary or Moyamoya Syndrome (MMS) when associated with underlying systemic conditions. While the RNF213 gene, particularly the p.R4810K variant, is recognized as the major susceptibility locus for MMD in East Asian populations, it does not fully account for the global genetic landscape or the phenotypic diversity of the disease. This review provides a comprehensive overview of the genetic architecture of the entire MMA spectrum, exploring loci beyond RNF213. We analyze the role of genes involved in vascular smooth muscle cell contractility (ACTA2, MYH11), TGF-β signaling, and DNA repair mechanisms that drive MMS, alongside the genetic basis of syndromic forms associated with neurofibromatosis type 1, trisomy 21, and RASopathies. Understanding these diverse genetic drivers is crucial for early diagnosis, risk stratification, and the development of targeted molecular therapies. Full article

Background: Non-invasive prenatal testing (NIPT) examines cell-free DNA (cfDNA) in maternal serum, which includes both maternal DNA and apoptotic placental DNA. The presence of multiple aneuploidies or widespread abnormal patterns of gains and losses across chromosomes in a structurally normal fetus has been linked to maternal cancer. Case Presentation: The patient was a 22-year-old G1P0 with a history of classical Hodgkin’s lymphoma in remission. Her NIPT collected at 14 weeks and 3 days was reported as a “no call”. A second NIPT at a different laboratory showed multiple chromosomal aneuploidies (trisomy 18, 21, and monosomy X) with normal fetal anatomy on ultrasound. The patient was asymptomatic and was referred to hematology–oncology specifically to address the concern that these NIPT results could be related to cancer recurrence. Imaging was deferred as she was already on an established surveillance protocol for her Hodgkin’s lymphoma. At 26 weeks of gestation, the patient presented with a cough and dyspnea. Chest x-ray raised concern for disease recurrence, and biopsy confirmed recurrent Hodgkin’s lymphoma. She received two cycles of ICE chemotherapy. Cesarean delivery at 34 weeks and 2 days was performed for non-reassuring fetal heart tones. She continued chemotherapy, followed by BEAM conditioning and autologous stem cell transplantation. Genetic testing of the neonate revealed a normal karyotype; the placenta karyotype yielded no interpretable results. Discussion and Conclusions: Certain patterns of abnormal NIPT results may be associated with maternal malignancy and warrant further investigation. The absence of standardized protocols for reporting such NIPT results can complicate timely interdisciplinary evaluation and treatment. However, diagnostic testing should be offered with a positive NIPT result, a no-call or test failure, and abnormal ultrasound results, even with a “low-risk” NIPT result. Full article

Objectives: This study aimed to examine the association between the dangling choroid plexus sign and fetal structural, chromosomal, and genetic abnormalities, as well as to define the normal range of lateral ventricular width and the ratio of choroid plexus width to lateral ventricular width at 14–17 weeks of gestation. Methods: This retrospective study analyzed ultrasound images from early fetal anatomy scans performed between January 2018 and July 2025 at two tertiary fetal medicine centres. In centre A, 6063 singleton pregnancies underwent routine scans at 11–13 and 14–17 weeks. In centre B, 776 fetuses with suspected abnormalities or increased nuchal translucency at 11–13 weeks were reassessed at 14–17 weeks. Additionally, 400 fetuses without obvious abnormalities at 14–17 weeks were used to determine normal ventricular measurements. Results: In normal fetuses, the mean lateral ventricular width was 6.90 mm (95% CI 6.81–6.99) and the mean choroid plexus-to-ventricle ratio was 0.85 (95% CI 0.84–0.86). A dangling choroid plexus was identified in 38 fetuses (0.16% in routine and 3.6% in high-risk populations). Out of 38 cases of dangling choroid plexus, 37 were associated with additional structural defects, chromosomal abnormalities, or single-gene disorders. Chromosomal abnormalities were found in 11/30 tested cases, most commonly trisomy 21. The most common defects observed on initial or subsequent scans were ventriculomegaly, cardiac defects, and abnormal posterior fossa. Conclusions: A dangling choroid plexus at 14–17 weeks is a sonographic marker associated with major fetal abnormalities and should prompt detailed anatomical assessment and consideration of genetic testing. Full article