OBJECTIVE: What is the influence of biological, technical and clinical factors on embryo outcomes in preimplantation genetic testing for aneuploidies (PGT-A) and what is the recurrence pattern?
METHODS: This retrospective study included 64,071 embryos undergoing PGT-A in the same laboratory between 2011 and 2019. Biopsies were performed at the day 3 embryo stage (48.32%) or blastocyst stage (51.70%). Advanced maternal age (AMA) was the main indication (65.62%).
RESULTS: The aneuploidy rate was 67.75%, higher in women aged over 35 years than in women aged 35 years or less (71.76% versus 47.44%), and higher in day 3 embryo versus blastocyst biopsies (77.51% versus 58.62%). The trisomy:monosomy ratio was 1.01 for blastocysts versus 0.84 for day 3 embryos. Trisomy 21 was present in 4.9% of embryos. In aneuploid embryos, the probability of having one or more involved chromosomes followed a decreasing exponential pattern. The probability of an embryo being euploid was constant at around 30% (40% in blastocysts, 20% in day 3 embryos). The cumulative probability of having one or more euploid embryos after 10 biopsied embryos was 94.79% in blastocysts and 80.61% in day 3 embryos. AMA was associated with a much higher aneuploidy rate than all other indications, which among them had similar aneuploidy rate and chromosomal involvement.
CONCLUSIONS: There is a considerably lower aneuploidy rate in blastocysts than day 3 embryos, which is most notable for monosomies. While AMA shows an increased aneuploidy rate and a specific chromosomal pattern of involvement, the remaining indications showed a similar aneuploidy rate and chromosomal pattern. Even after producing many consecutive aneuploid embryos, the possibility of obtaining a euploid embryo is not negligible.

47,XXX (Triple X syndrome) is a sex chromosome aneuploidy characterized by the presence of a supernumerary X chromosome in affected females and is associated with a variable cognitive, behavioral, and psychiatric phenotype. The effect of a supernumerary X chromosome in affected females on intracortical microstructure is currently unknown. Therefore, we conducted 7 Tesla structural MRI and compared T1 (ms), as a proxy for intracortical myelin (ICM), across laminae of 21 adult women with 47,XXX and 22 age-matched typically developing females using laminar analyses. Relationships between phenotypic traits and T1 values in 47,XXX were also investigated. Adults with 47,XXX showed higher bilateral T1 across supragranular laminae in the banks of the superior temporal sulcus, and in the right inferior temporal gyrus, suggesting decreases of ICM primarily within the temporal cortex in 47,XXX. Higher social functioning in 47,XXX was related to larger inferior temporal gyrus ICM content. Our findings indicate an effect of a supernumerary X chromosome in adult-aged women on ICM across supragranular laminae within the temporal cortex. These findings provide insight into the role of X chromosome dosage on ICM across laminae. Future research is warranted to further explore the functional significance of altered ICM across laminae in 47,XXX.

OBJECTIVE: Uterine fibroids are monoclonal tumors, which are often genetically abnormal and associated with false-positive genome-wide cell-free DNA (cfDNA) screening results, particularly when large. It is plausible that fibroids may also increase the risk of cfDNA failure by affecting fetal fraction or due to their genetic anomalies confounding cfDNA algorithms. We aimed to investigate a possible association between fibroids and cfDNA non-informative results.
METHODS: This was a retrospective cohort study of women undergoing cfDNA screening for fetal chromosomal abnormalities between 2013 and 2020, comparing pregnancies with vs without uterine fibroids recorded on any obstetric ultrasound before 24 weeks\' gestation. Univariable and multivariable logistic regression models were used to investigate the association between fibroids and cfDNA failure, adjusting for gestational age, maternal age, weight and height at blood sampling, mode of conception, multiple gestation and test platform (chromosome-selective or genome-wide). Analyses were stratified according to the number of fibroids and total fibroid volume. The impact of fibroids on fetal fraction was assessed using linear regression, adjusting for the same covariates.
RESULTS: Among 19 818 pregnancies undergoing cfDNA screening, fibroids were reported in 2038 (10.28%) and cfDNA failure at the first screening attempt occurred in 228 (1.15%) pregnancies. Non-informative results occurred in 1.96% of pregnancies with fibroids and 1.06% of pregnancies without fibroids (adjusted odds ratio (aOR), 2.40 (95% CI, 1.65-3.48)). The risk of failure in the first screening attempt increased progressively with the number of fibroids (aOR, 5.05 (95% CI, 2.29-11.13) in women with four or more fibroids) and total fibroid volume, with greater than a 5-fold and 14-fold increase in risk among women with fibroid volumes of 100.1-400 mL (aOR, 5.52 (95% CI, 2.30-13.25)) and > 400 mL (aOR, 14.80 (95% CI, 4.50-48.69)), respectively. Although test failure was more common with chromosome-selective than genome-wide screening, fibroids similarly increased the risk of failure of both screening platforms. Compared to pregnancies without fibroids, those with fibroids had a fetal fraction on average 0.61% lower (adjusted mean difference, -0.61% (95% CI, -0.77% to -0.45%)).
CONCLUSIONS: Uterine fibroids are associated with lower fetal fraction and an increased risk of cfDNA screening failure. The strength of this association increases with increasing fibroid number and volume. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVE: Recently, children with trisomy 18 have been receiving more active treatment for malignancies. We report herein seven cases complete resection was achieved, and discuss multidisciplinary treatment for hepatoblastoma in patients with trisomy 18.
METHODS: The medical records of children with trisomy 18 who were treated at the study center between 2010 and 2023 were reviewed.
RESULTS: Six of 69 patients had hepatoblastoma development, and three of these underwent multidisciplinary treatment. In addition, 6 patients had been referred by another hospital for treatment, and four of these underwent multidisciplinary treatment. Among the seven patients who underwent multidisciplinary treatment, three, two, and two were categorized in Pre-treatment Extent of Disease (PRETEXT) classification group I, II, and III, respectively. Neoadjuvant chemotherapy resulting in tumor reduction was performed in three cases. In all the cases, complete resection was achieved with pathologically safe margins. Perioperative complications included circulatory failure in one case and bile leakage in two cases. Adjuvant chemotherapy was administered in four cases. The postoperative observation period ranged from 3 months to 11 years, and all the patients are recurrence-free.
CONCLUSIONS: Children with trisomy 18 complicated with hepatoblastoma whose cardiopulmonary conditions are stable may be good candidates for chemotherapy and surgery.

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer\'s disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.

Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.

BACKGROUND: Extraneural metastasis of central nervous system tumors is generally rare and most often reported in glioblastomas and medulloblastomas, whereas oligodendrogliomas seem to have the lowest risk of extracranial metastasis. Given its infrequent occurrence, both the diagnosis and therapy of metastatic oligodendroglioma is often challenging.
METHODS: This case study presents an oligodendroglioma, the isocitrate dehydrogenase 1 (IDH1) mutant, 1p/19q-codeleted tumor with bone marrow metastasis. The significance of this case lies in the comprehensive molecular analysis conducted for both the primary tumor and the metastasis. Chromosome 7 trisomy and chromosome 10 monosomy (+ 7/-10) were detected in the metastasis indicating molecular progression, which, to the best of our knowledge, has not been previously documented in metastatic oligodendroglioma.
CONCLUSIONS: This case study serves additional information for better understanding of the metastatic capabilities of CNS tumors.

OBJECTIVE: To study whether gynecologic or reproductive disorders show association with trisomic conceptions.
METHODS: This nationwide cohort study utilized the Registry of Congenital Malformations to identify women who had a trisomic pregnancy (n = 5784), either with trisomy 13 (T13; n = 351), trisomy 18 (T18; n = 1065) or trisomy 21 (T21; n = 4369) from 1987 to 2018. We used the Finnish Maternity cohort to match the cases to population controls (n = 34 422) on the age, residence, and timing of pregnancy. These data were cross-linked to the ICD-10 diagnoses of the national Care Registry for Health Care data on specialized health care in Finland during 1996 to 2019. Both inflammatory (ICD-10 diagnoses: N70-N77) and noninflammatory disorders of the genital tract (N80-N98) were studied. Crude odds ratios (ORs) with 95% CIs were calculated for associations between diagnoses and trisomic conceptions.
RESULTS: The diagnosis of female infertility (N97) at any time was associated with trisomic conceptions (OR: 1.19, 95% CI: 1.08-1.32). In the subgroup analysis, this association was found for T18 (OR: 1.29, 95% CI: 1.03-1.61) and T21 (OR: 1.17, 95% CI: 1.04-1.32), but not for T13 (OR: 1.15, 95% CI: 0.75-1.72). When restricting the timing of the diagnosis of female infertility, an elevated OR was found only after the index pregnancy (OR: 1.81, 95% CI: 1.56-2.09). These increased odds for infertility after trisomic conceptions were observed both in women <35 years (T18 OR: 1.91, 95% CI: 1.21-3.00; T21 OR: 1.68, 95% CI: 1.31-2.14) and in women ≥35 years (T18 OR: 2.17, 95% CI: 1.40-3.33; T21 OR: 1.87; 95% CI: 1.47-2.39), but not after T13 conceptions.
CONCLUSIONS: Our observational data suggest a link between trisomic conceptions and subsequent diagnoses of infertility but do not demonstrate causality. These data implicate that partially similar mechanisms might predispose to trisomy and infertility, regardless of maternal age.

Sex chromosome aneuploidies (SCAs) collectively occur in 1 in 500 livebirths, and diagnoses in the neonatal period are increasing with advancements in prenatal and early genetic testing. Inevitably, SCA will be identified on either routine prenatal or newborn screening in the near future. Tetrasomy SCAs are rare, manifesting more significant phenotypes compared to trisomies. Prenatal cell-free DNA (cfDNA) screening has been demonstrated to have relatively poor positive predictive values (PPV) in SCAs, directing genetic counseling discussions towards false-positive likelihood rather than thoroughly addressing all possible outcomes and phenotypes, respectively. The eXtraordinarY Babies study is a natural history study of children prenatally identified with SCAs, and it developed a longitudinal data resource and common data elements with the Newborn Screening Translational Research Network (NBSTRN). A review of cfDNA and diagnostic reports from participants identified a higher than anticipated rate of discordance. The aims of this project are to (1) compare our findings to outcomes from a regional clinical cytogenetic laboratory and (2) describe discordant outcomes from both samples. Twenty-one (10%), and seven (8.3%) cases were found to be discordant between cfDNA (result or indication reported to lab) and diagnosis for the Babies Study and regional laboratory, respectively. Discordant results represented six distinct discordance categories when comparing cfDNA to diagnostic results, with the largest groups being Trisomy cfDNA vs. Tetrasomy diagnosis (66.7% of discordance in eXtraordinarY Babies study) and Mosaicism (57.1% in regional laboratory). Traditional genetic counseling for SCA-related cfDNA results is inadequate given a high degree of discordance that jeopardizes the accuracy of the information discussed and informed decision making following prenatal genetic counseling.

UNASSIGNED: Individuals with Down syndrome (DS) have intellectual disability and develop Alzheimer\'s disease (AD) pathology during midlife, particularly in the hippocampal component of the medial temporal lobe memory circuit. However, molecular and cellular mechanisms underlying selective vulnerability of hippocampal CA1 neurons remains a major knowledge gap during DS/AD onset. This is compounded by evidence showing spatial (e.g., deep versus superficial) localization of pyramidal neurons (PNs) has profound effects on activity and innervation within the CA1 region.
UNASSIGNED: We investigated whether there is a spatial profiling difference in CA1 PNs in an aged female DS/AD mouse model. We posit dysfunction may be dependent on spatial localization and innervation patterns within discrete CA1 subfields.
UNASSIGNED: Laser capture microdissection was performed on trisomic CA1 PNs in an established mouse model of DS/AD compared to disomic controls, isolating the entire CA1 pyramidal neuron layer and sublayer microisolations of deep and superficial PNs from the distal CA1 (CA1a) region.
UNASSIGNED: RNA sequencing and bioinformatic inquiry revealed dysregulation of CA1 PNs based on spatial location and innervation patterns. The entire CA1 region displayed the most differentially expressed genes (DEGs) in trisomic mice reflecting innate DS vulnerability, while trisomic CA1a deep PNs exhibited fewer but more physiologically relevant DEGs, as evidenced by bioinformatic inquiry.
UNASSIGNED: CA1a deep neurons displayed numerous DEGs linked to cognitive functions whereas CA1a superficial neurons, with approximately equal numbers of DEGs, were not linked to pathways of dysregulation, suggesting the spatial location of vulnerable CA1 PNs plays an important role in circuit dissolution.