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OBJECTIVE: While non-invasive prenatal testing (NIPT) has been widely adopted throughout Europe, Australia, and the USA, population level access to NIPT varies considerably. Ireland has no national screening programme for fetal anomalies, although NIPT is available from out-of-country providers. We aimed to describe the availability of NIPT in Ireland and the quality of information available online from NIPT providers. METHODS: Information available online from NIPT providers in the Republic of Ireland was analysed by examining all healthcare facilities websites and reviewing private health insurance directories. Data on information provided by NIPT providers was collected by two independent researchers from April to May 2023. RESULTS: Four of the 19 maternity hospitals/units in Ireland had information on NIPT on their websites, with three including an explanation of NIPT, testing accuracy, and associated fees (€380-480). Twenty private clinics led by obstetric consultants advertised NIPT online, of which seventeen clinics included an explanation of NIPT, testing accuracy, and associated fees (€380-€650). Twenty-nine other providers, which included ultrasound clinics, direct-to-consumer laboratory testing, and General Practitioners, advertised NIPT with 18 of these providers including an explanation of NIPT, testing accuracy, and associated fees (€179-€630). CONCLUSION: While there is apparent demand for NIPT and it is available in Ireland, there is disparity between providers on the type and quality of information available. Difficulty obtaining accessible information, the associated financial costs and location of providers advertising NIPT are likely to be barriers to accessing NIPT. A national screening programme for aneuploidy should be considered to ensure both equitable access to and reliable information about prenatal screening.

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Prenatal detection of copy number variants (CNVs) plays an important role in the diagnosis of fetal genetic abnormalities. Understanding the methods used for prenatal CNV detection and their clinical significance contributes to the implementation of advanced genetic screening techniques in prenatal care; facilitating early identification and management of genetic disorders in fetuses. Some CNVs impose significant genetic counselling challenges; especially those which are associated with uncertain clinical significance, in the context of variable penetrance and/or expressivity or when identified incidentally. This chapter focuses on the different techniques used for detecting CNVs, including Single Nucleotide Polymorphism (SNP) arrays, comparative genomic hybridization (CGH) arrays, Non-Invasive Prenatal Testing (NIPT), Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) as well as their advantages and limitations. The tools needed for the classification of CNVs and their clinical relevance are also explored, emphasising the importance of accurate interpretation for appropriate clinical management and genetic counselling.

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OBJECTIVE: This study aimed to comprehensively analyze the detection capacity of non-invasive prenatal testing (NIPT) for chromosomal abnormalities of all 24 chromosomes, as well as high-risk indications for pregnancy and the fetal fraction, in a large cohort. METHODS: We retrospectively enrolled 118,969 pregnant women who underwent NIPT at Sichuan Provincial Maternity and Child Health Care Hospital from March 2019 to June 2022. The sensitivity, specificity, positive predictive value, negative predictive value, and positive chromosomal abnormality rate were calculated. The fetal fraction based on gestational age, maternal body mass index, and number was examined. RESULTS: NIPT demonstrated > 99% sensitivity and specificity for almost all of the common trisomies (T21, T18, and T13), sex chromosomal aneuploidies, rare autosomal trisomies, and microdeletion/microduplication syndromes. Positive predictive values varied from 12.0% to 89.6%. Advanced maternal age was associated with an increased risk of three major aneuploidies. The fetal fraction was positively correlated with gestational age and negatively correlated with the maternal body mass index. CONCLUSIONS: NIPT can be used to effectively screen for chromosomal abnormalities across all 24 chromosomes. Advanced maternal age is a risk factor for high-risk pregnancy, and careful consideration of the fetal fraction is essential during NIPT.

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The Japanese government and medical professionals have negative attitudes toward the provision of prenatal testing and related information due to social concern regarding discrimination against persons with disabilities. However, with the rapid increase in the number of non-invasive prenatal tests, particularly at non-certificated medical facilities, in response to the growing demand from pregnant women, the Japanese government and medical professional associations have enacted radical changes marking an active commitment to the provision of information on these services. While a major justification for these policy changes is to ensure respect for reproductive autonomy and women's self-determination, they may reinforce the concern regarding discrimination. This article investigated the argument that these new policies may reinforce discrimination and examined three objections to this argument. The results revealed that the recent policy changes, particularly for specific fetal traits, may imply a negative belief about people living with the same traits. Consequently, fundamental institutional changes are necessary.

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Background: Polygenic risk scores (PRS) serve as valuable tools for connecting initial genetic discoveries with clinical applications in disease risk estimation. However, limited studies have explored the association between PRS and gestational diabetes mellitus (GDM), particularly in predicting GDM risk among Chinese populations. Aim: To evaluate the relationship between PRS and GDM and explore the predictive capability of PRS for GDM risk in a Chinese population. Methods: A prospective cohort study was conducted, which included 283 GDM and 2,258 non-GDM cases based on demographic information on pregnancies. GDM was diagnosed using the oral glucose tolerance test (OGTT) at 24-28 weeks. The strength of the association between PRS and GDM odds was assessed employing odds ratios (ORs) with 95% confidence intervals (CIs) derived from logistic regression. Receiver operating characteristic curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were employed to evaluate the improvement in prediction achieved by the new model. Results: Women who developed GDM exhibited significantly higher PRS compared to control individuals (OR = 2.01, 95% CI = 1.33-3.07). The PRS value remained positively associated with fasting plasma glucose (FPG), 1-hour post-glucose load (1-h OGTT), and 2-hour post-glucose load (2-h OGTT) (all p < 0.05). The incorporation of PRS led to a statistically significant improvement in the area under the curve (0.71, 95% CI: 0.66-0.75, p = 0.024) and improved discrimination and classification (IDI: 0.007, 95% CI: 0.003-0.012, p < 0.001; NRI: 0.258, 95% CI: 0.135-0.382, p < 0.001). Conclusions: This study highlights the increased odds of GDM associated with higher PRS values and modest improvements in predictive capability for GDM.

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Cell-free fetal DNA (cffDNA) screening is a valuable tool in clinical practice for detecting chromosomal abnormalities and autosomal dominant (AD) conditions. This study introduces a novel proof-of-concept assay designed for autosomal recessive (AR) cffDNA screening, focusing on cases involving the NPC1 gene. We aim to illustrate the significant benefits of AR cffDNA screening in managing high-risk pregnancies, specifically where biallelic pathogenic variants in NPC1 cause Niemann-Pick disease, type C1 (NPC), a disorder marked by progressive neurodegeneration. Three participants for this study were recruited and gave consent to a hospital in Saudi Arabia. These participants were either carriers of NPC or had a first- or second-degree relative affected by the disorder. No specific criteria were set for the age of the participants. All were between 15 and 18 weeks of gestation. Using amplicon-based next-generation sequencing (NGS), we analyzed the zygosity and variants in cffDNA extracted from maternal peripheral blood. After amplicon NGS, analysis was completed by a custom data analysis pipeline that included in-house-built data processing scripts and commonly used software packages. Importantly, the results were not disclosed to the patients. Our findings showed that in all three cases, AR cffDNA screening results were consistent with standard invasive diagnostic testing. This screening method offers several advantages: it provides critical information to families earlier in the pregnancy compared to invasive diagnostic tests, and it helps to alleviate parental anxiety. Moreover, this non-invasive method can determine pregnancy status in the first trimester for known familial variants. Future research may extend this approach to screen for known disease-causing variants in common AR conditions.

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A 31-year-old primiparous woman underwent non-invasive prenatal testing. The result was trisomy 13 (T13) positive. The chromosome 13 t-statistics (Z-score) was significantly high. The result of amniocentesis was normal karyotype (46,XX). Detailed ultrasound showed no fetal structural abnormalities. We suspected T13 confined placental mosaicism (CPM) and observed the course naturally. From the late second trimester, severe fetal growth restriction manifested followed by proteinuria and hypertension, diagnosing her with preeclampsia (PE). At 35 + 5 weeks, emergent cesarean section was required, yielding a 1480 g female infant. We sampled five locations of chorionic villi in the placenta. T13 cells dominated cells with normal karyotypes in all parts and the rate of trisomic cells ranged from 57% to 96%, which were generally high rate. None developed PE in reported T13 CPM cases and this is the first case of PE. The dominancy of T13 cells can be associated with PE development.

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Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. Unbalanced chromosome abnormalities are either gains or losses of large genomic regions that do not or only minimally clinically affect the individual. Noninvasive prenatal testing (NIPT) is widely used in the screening of common fetal chromosome aneuploidy. One example is the duplication of 10q11.21q11.23, which includes the 10q11.2 region. This region contains a complex set of low-copy repeats that may lead to various genomic alterations through non-allelic homologous recombination. In this report, we present a case of a de novo 10q11.21q11.23 duplication with a normal phenotype. This case may be helpful for prenatal diagnosis and genetic counseling. A combination of NIPT, prenatal ultrasound, karyotype analysis, copy number variation sequencing, and genetic counseling is helpful for the prenatal diagnosis of CNVs.

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Background/Objectives: Cell-free DNA (cfDNA) is a non-invasive prenatal test used to screen for common trisomies (target cfDNA) that can be expanded to assess all autosomal chromosomes (genome-wide cfDNA). As cfDNA testing gains popularity, it is crucial to examine the factors influencing the decision-making process of pregnant individuals when choosing between these two approaches. Methods: In this prospective cohort study, 190 individuals undergoing cfDNA testing for aneuploidy screening, according to the current screening protocol, were allowed to make their own choice between target and genome-wide cfDNA testing. They were asked to complete a first survey at 11-13 weeks, designed to explore their characteristics, preferences, and satisfaction with the prenatal genetic counseling session, as well as a Decisional Conflict Scale. A postnatal survey was administered three months after delivery, including the Decisional Regret Scale and two open questions. Results: 84% of participants opted for genome-wide cfDNA. However, 17% found the decision challenging, and 14% felt that the results might increase anxiety. No significant differences in participant characteristics were found when comparing decisions between genome-wide and target cfDNA. However, significant differences were observed regarding ethnicity (p = <0.001), educational level (p = 0.029), previous cfDNA experience (p = 0.004), and having sufficient information when comparing termination options (p = 0.002). After delivery, only 4% would have changed their decision. Conclusions: Individuals, regardless of their characteristics, prefer genome-wide cfDNA; however, the complexity of the results necessitates enhanced genetic education for prenatal care clinicians.

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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%)). CONCLUSION: 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.

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BACKGROUND: Noninvasive prenatal testing (NIPT) was developed to improve the accuracy of prenatal screening to detect chromosomal abnormalities. Published economic analyses have yielded different incremental cost-effective ratios (ICERs), leading to conclusions of NIPT being dominant, cost-effective, and cost-ineffective. These analyses have used different model structures, and the extent to which these structural variations have contributed to differences in ICERs is unclear. AIM: To assess the impact of different model structures on the cost-effectiveness of NIPT for the detection of trisomy 21 (T21; Down syndrome). METHODS: A systematic review identified economic models comparing NIPT to conventional screening. The key variations in identified model structures were the number of health states and modeling approach. New models with different structures were developed in TreeAge and populated with consistent parameters to enable a comparison of the impact of selected structural variations on results. RESULTS: The review identified 34 economic models. Based on these findings, demonstration models were developed: 1) a decision tree with 3 health states, 2) a decision tree with 5 health states, 3) a microsimulation with 3 health states, and 4) a microsimulation with 5 health states. The base-case ICER from each model was 1) USD$34,474 (2023)/quality-adjusted life-year (QALY), 2) USD$14,990 (2023)/QALY, (3) USD$54,983 (2023)/QALY, and (4) NIPT was dominated. CONCLUSION: Model-structuring choices can have a large impact on the ICER and conclusions regarding cost-effectiveness, which may inadvertently affect policy decisions to support or not support funding for NIPT. The use of reference models could improve international consistency in health policy decision making for prenatal screening. HIGHLIGHTS: NIPT is a clinical area in which a variety of modeling approaches have been published, with wide variation in reported cost-effectiveness.This study shows that when broader contextual factors are held constant, varying the model structure yields results that range from NIPT being less effective and more expensive than conventional screening (i.e., NIPT was dominated) through to NIPT being more effective and more expensive than conventional screening with an ICER of USD$54,983 (2023)/QALY.Model-structuring choices may inadvertently affect policy decisions to support or not support funding of NIPT. Reference models could improve international consistency in health policy decision making for prenatal screening.

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Introduction: Pregnant women can choose from different prenatal genetic tests throughout their maternity journey. We aim to investigate the clinical, societal, and economic determinants influencing the selection of different options (non-invasive, invasive, or both). Methods: A systematic survey focusing on maternity pathways was launched by the Region of Tuscany, Italy, to collect data on pregnant women's experience, outcomes and satisfaction levels. Drawing from this survey, we retrospectively analyzed data on women who filled out the second-trimester questionnaire between March 2019 and February 2023 (n = 27,337), providing complete data on relevant variables. Logistic regression models were applied to identify the factors contributing to a higher likelihood of opting for non-invasive prenatal testing (NIPT) and invasive testing. Results: Among the participants, 42.7 % chose only NIPT, 3.8 % opted for invasive tests exclusively, 1.3 % underwent both tests, and 52.2 % did not pursue any genetic testing. NIPT was more often chosen by older, Italian, highly educated, nulliparous women, who perceived better health, were employed (versus unemployed), had higher economic status, planned pregnancy, received hospital-based care (versus counseling center), under gynecologist supervision (versus midwife), not opted for combined testing and received pregnancy vaccinations. Conversely, invasive testing was more prevalent among older women but less common among those who were nulliparous, had Italian nationality, and had a perceived better health status. This group also tended to experience unplanned and high-risk pregnancy, did not take folate during pregnancy, received public hospital-based assistance, less frequently chose combined tests or NIPT, and had frequent delays in examinations. Conclusions: Various factors beyond clinical considerations influence the selection of a prenatal test. Therefore, NIPT pathways should include balanced, high-quality information about benefits and limitations, ensuring laboratory specialists' active and integrated involvement in decision-making.

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The international community has proposed a comprehensive strategy to prevent congenital abnormalities. And China, with a high incidence of congenital diseases, has implemented measures including prenatal screening and diagnosis to reduce the morbidity of congenital abnormalities. However, ethical challenges arise in the practice of prenatal screening and diagnosis among healthcare professionals. Five focus group discussions were conducted with twenty-four health professionals working in maternal and child health services in Hunan Province, China, to explore the ethical challenges they encountered in prenatal testing decision-making and information disclosure practices, as well as their views on these challenges. Participants were selected through purposive sampling, ensuring maximum demographic diversity. Three main themes were identified: 1) balancing between information disclosure and privacy protection; 2) patient-oriented decision-making and tensions within family-oriented decision-making; 3) the disparity between the limited help clinical ethics committees (CECs) can provide and professionals' need for CECs. Ethical norms for information disclosure and autonomous decision-making within prenatal screening and diagnostic institutions must be established. Utilizing CECs is crucial to guide professionals in delivering prenatal testing services while simultaneously focusing on targeted improvement of communication skills among these professionals.

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This EBCOG guidance reviews the current and future status of genomics within fetal and maternal medicine. This document addresses the clinical uses of genetic testing in both screening and diagnostic testing prenatally. The role of genomics within fetal and maternal medicine is described. The research and future implications of genetic testing as well as the educational, ethical and economic implications of genomics are discussed.

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BACKGROUND: Digital Polymerase Chain Reaction (dPCR) presents a promising approach for quantifying DNA and analyzing copy number variants, particularly in non-invasive prenatal testing. This method offers a streamlined and time-efficient procedure in contrast to the widely used next-generation sequencing for non-invasive prenatal testing. Studies have reported encouraging results for dPCR in detecting fetal autosomal aneuploidies. Consequently, this systematic review aimed to evaluate the effectiveness of dPCR in screening for trisomy 21, 18, and 13. METHODS: A systematic search was conducted in PubMed, Web of Sciences, and Embase for relevant articles published up to December 30, 2023. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was utilized for the quality assessment of the included articles. Furthermore, a bivariate random-effect regression model was used to conduct a meta-analysis on the utility of dPCR for trisomy 21 screening. RESULTS: A total of 9 articles were included in this review, with all of them assessing the utility of dPCR in trisomy 21 screening, and 2 and 1 studies conducting additional analysis on the screening abilities of dPCR for trisomy 18 and 13, respectively. A bivariate random-effects model calculated pooled sensitivity and specificity with a 95% confidence interval (CI). Meta-analysis of 6 studies comparing trisomy-21 screening with karyotyping demonstrated dPCR's pooled sensitivity of 98% [95% CI: 94 -100] and specificity of 99% [95% CI: 99 -100]. While conducting a meta-analysis for trisomy 13 and 18 proved impractical, reported values for sensitivity and specificity were favorable. CONCLUSIONS: These findings suggest that dPCR holds promise as an effective tool for non-invasive prenatal testing, presenting a less time-consuming and intricate alternative to next-generation sequencing. However, further research is necessary to evaluate dPCR's applicability in clinical settings and to delineate its specific advantages over next-generation sequencing. This study contributes valuable insights into the potential of dPCR for enhancing prenatal screening methodologies. TRIAL REGISTRATION: The protocol of this study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) on 7/3/2024, with a registration code of CRD42024517523.

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INTRODUCTION: Ongoing advances in genetic technology may soon provide prenatal screening for multiple genetic conditions. AIMS: The aims were to investigate what prenatal screening test characteristics women prioritise and their willingness to pay for these tests. METHODS: We designed an online survey incorporating a series of discrete choice scenarios. Dimensions and levels were selected based on existing prenatal tests and a hypothetical prenatal test that could non-invasively detect multiple genetic disorders in pregnancy. Participants were recruited from social media platforms. Data were analysed using conditional logistic regression and latent class analysis (LCA). RESULTS: A total of 219 women completed the survey. Women with higher incomes and those with a tertiary education were willing to pay more than other groups. The maximum willingness to pay was AUD1870 (95% confidence interval: 1630, 2112) for a hypothetical non-invasive test to detect multiple genetic conditions in early pregnancy. An LCA demonstrated considerable heterogeneity in preferences, differing in both overall preference for testing and test characteristics considered most attractive. Among the participants, decision factors cited by 14.5% of participants were the risk of pregnancy loss, making them less likely to undergo testing; for 32.1% participants, accuracy was a major factor, and they were very likely to have testing; for 12.9%, test availability early in pregnancy was a decision factor. CONCLUSIONS: If a non-invasive test that could detect the greatest number of genetic disorders in pregnancy was available, the priorities were test accuracy, risk of pregnancy loss and a test available early in pregnancy.

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Advances in technology have correlated with expanding prenatal genetic testing options for pregnant people. Leading medical organizations recommend cell-free DNA as the most sensitive screening test for trisomies 13, 18, and 21, as well as for fetal sex chromosome aneuploidies. The commercially available testing options go beyond these recommended tests, and prenatal care professionals should be familiar with the tests that their patients may choose despite being beyond the scope of current medical recommendations. This article explains updates in cell-free DNA technology and clinical considerations for prenatal care professionals, recognizing that this is a rapidly changing field of science and health care.

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OBJECTIVE: To evaluate the accuracy of expanded noninvasive prenatal testing (NIPT) for maternal copy number variations. MATERIALS AND METHODS: Expanded NIPT was used to detect CNVs ≥2 Mb at a whole-genome scale. The threshold of maternal deletion was copy numbers (CN) ≤ 1.6, and the threshold of maternal duplication was CN ≥ 2.4. RESULTS: Of the 5440 pregnant women with successful expanded NIPT results, 28 maternal CNVs ≥2 Mb were detected in 27 pregnant women. Except for five cases reported as test failure, 23 CNVs ≥2 Mb were confirmed among the remaining 22 pregnant women by CNV-seq of maternal lymphocyte DNA. The genomic location, copy numbers and fragment size of maternal CNVs reported by expanded NIPT were consistent with the results of CNV-seq of maternal lymphocyte DNA. CONCLUSIONS: Maternal CNVs ≥2 Mb can be accurately evaluated according to the CN indicated by expanded NIPT results.

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PURPOSE: The aim of this study was to examine whether there is a correlation between different types of ventricular septal defects (VSD) and chromosomal abnormalities in the low-risk setting of non-invasive prenatal testing (NIPT) and to evaluate the prognosis of fetuses with varying types of VSD. METHODS: Cases of pregnant women who underwent amniocentesis due to fetal VSD were collected by Tianjin Central Hospital of Obstetrics and Gynecology from May 2017 to May 2022. Exclusions were made for those without NIPT, with high-risk NIPT results, genetic disorders, and those lost to follow-up. Data collected included ultrasound classification of VSD, prenatal NIPT results, copy-number variations (CNVs) results, and neonatal outcomes. RESULTS: The prevalence of pathogenic CNVs was investigated in 74 cases of VSDs. Of these cases, 45 were isolated VSDs (9 muscular and 36 non-muscular) and 29 were non-isolated VSDs (10 with intracardiac and 19 with extra-cardiac structural anomalies). The results revealed that the incidence of pathogenic CNVs was lower in isolated VSDs compared to non-isolated VSDs in a low-risk NIPT condition (χ2 = 9.344, P = 0.002). There was no significant difference in the prevalence of pathogenic CNVs between VSDs with intracardiac and extra-cardiac structural anomalies (P = 0.541). Moreover, VSDs associated with intracardiac structural anomalies had the highest rate of surgical intervention. CONCLUSION: When NIPT is low-risk and VSD is isolated, the likelihood of fetal chromosomal defects is not increased. However, if there are intra- or extra-cardiac structural abnormalities present alongside VSD, the possibility of pathogenic CNV is considerably greater, necessitating invasive prenatal diagnosis. Isolated muscular VSDs usually do not require surgery, which can be used as a basis for prenatal counseling regarding fetal VSD.

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Non-invasive prenatal testing (NIPT) is a quite popular approach for detecting fetal genomic aneuploidies. However, due to the limitations on sequencing read length and coverage, NIPT suffers a bottleneck on further improving performance and conducting earlier detection. The errors mainly come from reference biases and population polymorphism. To break this bottleneck, we proposed NIPT-PG, which enables the NIPT algorithm to learn from population data. A pan-genome model is introduced to incorporate variant and polymorphic loci information from tested population. Subsequently, we proposed a sequence-to-graph alignment method, which considers the read mis-match rates during the mapping process, and an indexing method using hash indexing and adjacency lists to accelerate the read alignment process. Finally, by integrating multi-source aligned read and polymorphic sites across the pan-genome, NIPT-PG obtains a more accurate z-score, thereby improving the accuracy of chromosomal aneuploidy detection. We tested NIPT-PG on two simulated datasets and 745 real-world cell-free DNA sequencing data sets from pregnant women. Results demonstrate that NIPT-PG outperforms the standard z-score test. Furthermore, combining experimental and theoretical analyses, we demonstrate the probably approximately correct learnability of NIPT-PG. In summary, NIPT-PG provides a new perspective for fetal chromosomal aneuploidies detection. NIPT-PG may have broad applications in clinical testing, and its detection results can serve as a reference for false positive samples approaching the critical threshold.

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