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BackgroundThis paper evaluated the clinical utility of massively parallel sequencing-based non-invasive prenatal testing (NIPT) for detecting trisomy 21 (T21), T18, T13, sex chromosome aneuploidies (SCA), and rare chromosome aneuploidies (RCA) among the data collected by a clinical laboratory in southern China.MethodsIn a 3-year period between January 2017 and December 2019, over 40,000 pregnant women underwent NIPT clinical screening test for fetal T21, T18, T13, SCA, and RCA in our laboratory. NIPT samples were processed using the NextSeq CN500 platform. The positive results were confirmed by karyotyping, and chromosomal microarray analysis (CMA) or copy number variants (CNV) sequencing. Details of the pregnancy outcomes were collected via telephone interview.ResultsNIPT results were available for 41,819 cases; 691 positive cases were reported. The overall sensitivity for detection of T21, T18, T13, SCA, and RCA was 99.21, 100.00, 100.00, 98.55, and 100.00%, and the specificity was 99.95, 99.94, 99.98, 99.69, and 99.92%, respectively. The positive predictive values (PPVs) for detection of T21, T18, T13, SCA, and RCA were 85.62, 45.24, 40.00, 34.17, and 13.51%, respectively, and those for detection of 45,X, 47,XXY, 47,XXX, 47,XYY, and 46,XY(delX) 20.00, 59.18, 28.95, 61.54, and 25.00%, respectively. Regarding pregnancy outcomes, 92.38% of the pregnancies with confirmed aneuploidies were terminated, and 91.20% of those identified as having a false-positive result were carried to term. Among 252 unconfirmed cases, 24.60% of the pregnancies were terminated and 38.10% carried to term, while 37.30% declined interview.ConclusionsNIPT is widely used to screen fetal aneuploidies based on its high sensitivity and specificity. However, in this study, the PPVs of NIPT in terms of detecting T18, T13, XO, XXX and RCA were < 50%. In addition, more than one-third of NIPT-positive women did not accept invasive prenatal diagnosis. Confirmatory diagnosis is strongly recommended for women with positive NIPT outcomes before any further decision is made.

Background Noninvasive prenatal testing (NIPT) for fetal aneuploidies by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a first-tier aneuploidy screening test in clinical practices. With the development of whole-genome sequencing technology, small subchromosomal deletions and duplications that could not be detected by conventional karyotyping are now able to be detected with NIPT technology. Methods In the present study, we examined 8141 single pregnancies with NIPT to calculate the positive predictive values of each of the chromosome aneuploidies and the subchromosomal microdeletions and microduplications. Results We confirmed that the positive predictive values (PPV) for trisomy 13, trisomy 18, trisomy 21, and sex chromosome aneuploidy were 14.28%, 60%, 80%, and 45.83%, respectively. At the same time, we also found 51 (0.63%) positive cases for chromosomal microdeletions or microduplications but only 13 (36.11%) true-positive cases. These results indicate that NIPT for trisomy 21 detection had the highest accuracy, while accuracy was low for chromosomal microdeletion and microduplications. Conclusions Therefore, it is very important to improve the specificity, accuracy, and sensitivity of NIPT technology for the detection of subchromosomal microdeletions and microduplications.

Introduction To assess the clinical efficacy of prenatal cfDNA screening for detecting sex chromosome aneuploidies (SCAs). Material and Methods We conducted a retrospective study at a single center including women with singleton pregnancies who underwent prenatal cfDNA screening between January 2020 and December 2024. Cases with high‐risk cfDNA screening results for SCAs were reviewed for confirmatory diagnostic results, prenatal ultrasound findings, and pregnancy outcomes. Positive predictive values (PPVs) were calculated for each SCA subtype, and associations between ultrasound findings and confirmed SCAs were analyzed. Results A total of 252 pregnancies (252/58720, 0.43%) were identified as high‐risk cfDNA screening results for SCAs, including 224 fetal and 28 maternal cases. The fetal SCAs comprised 101 cases of 45,X, 37 of 47,XXX, 55 of 47,XXY, and 31 of 47,XYY. Among them, 173 underwent invasive diagnosis, confirming 90 true SCA cases with a PPV of 52.0%. For 45,X, there was a trend toward a higher detection rate in those with abnormal ultrasound findings compared to those with normal ultrasound results (4/20 vs. 8/127, p = 0.060), though it did not reach statistical significance; no significant differences were observed for sex chromosome trisomies. Of the 16 maternal SCA cases that underwent invasive testing, all fetuses had normal karyotypes. Conclusions Our findings demonstrated prenatal cfDNA screening as a unique approach to achieve effective detection of fetal SCAs, particularly those that otherwise would be overlooked by routine prenatal ultrasound screening. CfDNA screening effectively detected SCAs often undetected by routine prenatal ultrasound. Maternal SCAs showed rare fetal transmission.

Cancer cells are known to have chromosomal number abnormalities (aneuploidy), a hallmark of malignant tumors. Cancer cells also have an increased number of centrosomes (centrosome amplification). Paradoxically, cancer therapies, including γ-irradiation and some anticancer drugs, are carcinogenic and can induce centrosome amplification and chromosomal aneuploidy. Thus, the processes of carcinogenesis and killing cancer cells might have some mechanisms in common. Previously, we found that the inhibitors of polyADP-ribosylation, a post-translational modification of proteins, caused centrosome amplification. However, the mechanism of action of the inhibitors of polyADP-ribosylation is not fully understood. In this study, we found that an inhibitor of polyADP-ribosylation, 3-aminobenzamide, caused centrosome amplification, as well as aneuploidy of chromosomes in CHO-K1 cells. Moreover, inhibitors of polyADP-ribosylation inhibited AKT phosphorylation, and inhibitors of AKT phosphorylation inhibited polyADP-ribosylation, suggesting the involvement of polyADP-ribosylation in the PI3K/Akt/mTOR signaling pathway for controlling cell proliferation. Our data suggest a possibility for developing drugs that induce centrosome amplification and aneuploidy for therapeutic applications to clinical cancer.

The liver is increasingly recognized as a major regulator of systemic cardio‐renal‐metabolic health. Evidence is mounting that sex‐chromosome dosage per se itself, independent of gonadal sex hormones, modulates hepatic physiology and liver disease risk. Turner syndrome (TS; monosomy X) and Klinefelter syndrome (KS; 47, XXY and variants) are the two most common sex‐chromosome aneuploidies and carry a clinically relevant, yet often under‐appreciated, burden of liver disease. Population studies show that individuals with TS have 2‐ to sixfold higher odds of raised liver enzymes, steatotic liver disease, advanced fibrosis, and even hepatocellular malignancy compared with to sex‐ and age‐matched controls. In KS, the prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) reaches approximately 45%, with testosterone deficiency, visceral adiposity, and systemic inflammation acting as key drivers. Pathogenetic mechanisms converge on vascular dysgenesis and estrogen deficiency in TS, and on hypogonadism‐related metabolic derangements in KS, together accelerating steatosis, inflammation, and fibrogenesis. This concise review/Comprehensive perspective reviews discusses historical background, epidemiology, hepatic phenotypes, pathophysiology, and current diagnostic and management recommendations. It also highlights critical knowledge gaps, including the need for prospective cohorts, optimized hormone‐replacement protocols, and trials of emerging pharmacological approaches anti‐MASH agents. Raising awareness among all stakeholders, endocrinologists, hepatologists, and primary‐care physicians is essential for early detection, multidisciplinary management, and improved hepatic and extra‐hepatic outcomes in these vulnerable patient populations. Summary Evidence from experimental studies suggests that X and Y chromosome complements may independently regulate adiposity, inflammation, and metabolic pathways. Two human disorders, Turner syndrome (TS) and Klinefelter syndrome (KS), help address the research question of whether sex chromosomes themselves directly influence liver health, beyond their role in determining gonadal function through differentially expressed genes involved in various aspects of cellular function and integrity. TS and KS, the two most common sex‐chromosome aneuploidies, exhibit hypogonadism as well as cardiovascular, renal, and metabolic issues. Recent evidence also indicates a significant burden of liver disease in both syndromes. Hepatic involvement in TS and KS ranges from mild enzyme elevations to conditions like steatosis, steatohepatitis, fibrosis, and cirrhosis in some patients. This is crucial because the liver's impact on cardiovascular, kidney, and metabolic health implies that advanced fibrosis in TS and KS has broader implications for overall morbidity and mortality beyond just liver‐related outcomes.

Aneuploidy causes changes in gene expression and phenotypes in all organisms studied. A previous study in the model plant Arabidopsis thaliana showed that aneuploidy‐generated phenotypic changes can be inherited to euploid progenies and implicated an epigenetic underpinning of the heritable variations. Based on an analysis by amplified fragment length polymorphism and methylation‐sensitive amplified fragment length polymorphism markers, we found that although genetic changes at the nucleotide sequence level were negligible, extensive changes in cytosine DNA methylation patterns occurred in all studied homeologous group 1 whole‐chromosome aneuploid lines of common wheat (Triticum aestivum), with monosomic 1A showing the greatest amount of methylation changes. The changed methylation patterns were inherited by euploid progenies derived from the aneuploid parents. The aneuploidy‐induced DNA methylation alterations and their heritability were verified at selected loci by bisulfite sequencing. Our data have provided empirical evidence supporting earlier suggestions that heritability of aneuploidy‐generated, but aneuploidy‐independent, phenotypic variations may have an epigenetic basis. That at least one type of aneuploidy – monosomic 1A – was able to cause significant epigenetic divergence of the aneuploid plants and their euploid progenies also lends support to recent suggestions that aneuploidy may have played an important and protracted role in polyploid genome evolution.

In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are downregulated but most differentially expressed inactive genes are upregulated. In KS, differentially expressed escape genes are upregulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (RPS4X, SEPT6, NKRF, CX0rf57, NAA10, and FLNA) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.

Background Since the discovery of cell-free DNA (cfDNA) in maternal plasma, it has opened up new approaches for non-invasive prenatal testing. With the development of whole-genome sequencing, small subchromosomal deletions and duplications could be found by NIPT. This study is to review the efficacy of NIPT as a screening test for aneuploidies and CNVs in 42,910 single pregnancies. Methods A total of 42,910 single pregnancies with different clinical features were recruited. The cell-free fetal DNA was directly sequenced. Each of the chromosome aneuploidies and the subchromosomal microdeletions/microduplications of PPV were analyzed. Results A total of 534 pregnancies (1.24%) were abnormal results detected by NIPT, and 403 pregnancies had underwent prenatal diagnosis. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), and other chromosome aneuploidy was 79.23%, 54.84%, 13.79%, 33.04%, and 9.38% respectively. The PPV for CNVs was 28.99%. The PPV for CNVs ≤ 5 Mb is 20.83%, for within 5–10 Mb 50.00%, for > 10 Mb 27.27% respectively. PPVs of NIPT according to pregnancies characteristics are also different. Conclusion Our data have potential significance in demonstrating the usefulness of NIPT profiling not only for common whole chromosome aneuploidies but also for CNVs. However, this newest method is still in its infancy for CNVs. There is still a need for clinical validation studies with accurate detection rates and false positive rates in clinical practice.

Background Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific tissues, and thereby having clinical implication for the phenotype, remains to be elucidated. Methods We performed a comprehensive analysis of X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue from individuals with 45,X, 46,XX, 46,XY, and 47,XXY. Results X chromosome number affected the transcriptome and methylome globally across all chromosomes in a tissue-specific manner. Furthermore, 45,X and 47,XXY demonstrated a divergent pattern of gene expression and methylation, with overall gene downregulation and hypomethylation in 45,X and gene upregulation and hypermethylation in 47,XXY. In fat and muscle, a pronounced effect of sex was observed. We identified X chromosomal genes with an expression pattern different from what would be expected based on the number of X and Y chromosomes. Our data also indicate a regulatory function of Y chromosomal genes on X chromosomal genes. Fourteen X chromosomal genes were downregulated in 45,X and upregulated in 47,XXY, respectively, in all three tissues ( AKAP17A , CD99 , DHRSX , EIF2S3 , GTPBP6 , JPX , KDM6A , PP2R3B , PUDP , SLC25A6 , TSIX , XIST , ZBED1 , ZFX ). These genes may be central in the epigenetic and genomic regulation of sex chromosome aneuploidies. Conclusion We highlight a tissue-specific and complex effect of X chromosome number on the transcriptome and methylome, elucidating both shared and non-shared gene-regulatory mechanism between SCAs.

Background Early miscarriage, a common pregnancy complication predominantly occurring before 12 weeks, is conclusively linked to embryonic chromosomal abnormalities. Given the rising proportion of pregnancies at advanced maternal age, a contemporary re-examination of the relationships among early miscarriage, sex chromosomal anomalies, and maternal age is imperative to optimize clinical counseling strategies. Methods This retrospective study analyzed cases from the Medical Genetics and Prenatal Diagnosis Center at the Third Affiliated Hospital of Zhengzhou University (July 2022–December 2024). Inclusion criteria required fetal samples with < 10% maternal cell contamination confirmed by fluorescent PCR-capillary electrophoresis. Exclusion criteria included absence of CNV-seq/CMA testing results, discordant results, incomplete documentation, or donor oocyte pregnancies. Cases were stratified into early miscarriage (EM) group and non-EM (NEM) group. Chromosomal abnormalities (triploidy/tetraploidy, uniparental disomy and aneuploidies involving chromosomes 21, 18, 13, X, and Y), fetal sex, and maternal age were compared between groups. Results In a cohort of 21,311 fetuses undergoing genetic testing, the overall prevalence of sex chromosome aneuploidies (SCAs) was 2.07%. Fetuses with EM exhibited significantly higher SCAs prevalence (7.5%) compared to NEM (1.4%, P  < 0.001). Stratified analysis demonstrated elevated 45, X/mosaic 45, X frequency in EM (7.03% vs. 0.40% NEM, P  < 0.001), whereas XYY/XXY/XXX/mosaic XXX was significantly lower in EM (0.34% vs. 0.97% NEM, P  = 0.002). The EM rate increased with maternal age from 15 to 27 years, stabilized around 13% thereafter, and showed minor fluctuations. Maternal age was significantly lower in cases with 45,X compared to other cases (29.88 ± 4.15 vs. 31.43 ± 4.50 years, P  < 0.001). Conclusions This observational study identified an overall SCAs prevalence of 2.07% in the cohort. Beyond sex chromosome trisomies, autosomal trisomies and 45, X demonstrated higher prevalence in the EM compared to NEM. A positive correlation existed between chromosomal trisomies prevalence and advancing maternal age, whereas 45, X exhibited inverse association with maternal aging. Distinct age-stratified pattern emerged: early miscarriage rates increased with maternal age before 27 years, stabilizing thereafter at approximately 13% without further age-dependent fluctuations.