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The objective of the study was to identify the types of studies and the most investigated topics in the population with Down syndrome in Chile and to describe the type of sample used and the age range during the period from 2011 to 2020. A documentary study was carried out (systematic review). The Scopus database was used to search for information. The key words used were: Down Syndrome and Chile. The period was 2011 to 2020. The information was recorded on an observation sheet. Thirty studies were identified. A total of 56,7 % (n = 17) were descriptive (cross-sectional) studies, 10,0 % (n = 3) were experimental studies. The study topics mostly cover social issues (8 studies) and anthropometric aspects (7 studies), followed by physiological, psychological, hematological, biomechanical, prenatal tests and sleep disorders. The age range of the sample used by the studies ranges from prenatal to 28 years and the sample size ranges from one to 1922 participants. The results of the study suggest the urgent need to develop experimental and longitudinal studies, the inclusion of middle-aged and older adults, as well as prenatal samples, to explore issues related to physiological, psychological, hematological, biomechanical variables and prenatal diagnostic tests, since they are relevant to the independence and autonomy of people with Down syndrome. [ABSTRACT FROM AUTHOR]

Soft markers were originally introduced to prenatal ultrasonography to improve the detection of trisomy 21 over that achievable with age-based and serum screening strategies. As prenatal genetic screening strategies have greatly evolved in the last 2 decades, the relative importance of soft markers has shifted. The purpose of this document is to discuss the recommended evaluation and management of isolated soft markers in the context of current maternal serum screening and cell-free DNA screening options. In this document, "isolated" is used to describe a soft marker that has been identified in the absence of any fetal structural anomaly, growth restriction, or additional soft marker following a detailed obstetrical ultrasound examination. In this document, "serum screening methods" refers to all maternal screening strategies, including first-trimester screen, integrated screen, sequential screen, contingent screen, or quad screen. The Society for Maternal-Fetal Medicine recommends the following approach to the evaluation and management of isolated soft markers: (1) we do not recommend diagnostic testing for aneuploidy solely for the evaluation of an isolated soft marker following a negative serum or cell-free DNA screening result (GRADE 1B); (2) for pregnant people with no previous aneuploidy screening and isolated echogenic intracardiac focus, echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1B); (3) for pregnant people with no previous aneuploidy screening and isolated thickened nuchal fold or isolated absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening through cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (4) for pregnant people with no previous aneuploidy screening and isolated choroid plexus cysts, we recommend counseling to estimate the probability of trisomy 18 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1C); (5) for pregnant people with negative serum or cell-free DNA screening results and an isolated echogenic intracardiac focus, we recommend no further evaluation as this finding is a normal variant of no clinical importance with no indication for fetal echocardiography, follow-up ultrasound imaging, or postnatal evaluation (GRADE 1B); (6) for pregnant people with negative serum or cell-free DNA screening results and isolated fetal echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend no further aneuploidy evaluation (GRADE 1B); (7) for pregnant people with negative serum screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and discussion of options for no further aneuploidy evaluation, noninvasive aneuploidy screening through cell-free DNA, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (8) for pregnant people with negative cell-free DNA screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend no further aneuploidy evaluation (GRADE 1B); (9) for pregnant people with negative serum or cell-free DNA screening results and isolated choroid plexus cysts, we recommend no further aneuploidy evaluation, as this finding is a normal variant of no clinical importance with no indication for follow-up ultrasound imaging or postnatal evaluation (GRADE 1C); (10) for fetuses with isolated echogenic bowel, we recommend an evaluation for cystic fibrosis and fetal cytomegalovirus infection and a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C); (11) for fetuses with an isolated single umbilical artery, we recommend no additional evaluation for aneuploidy, regardless of whether results of previous aneuploidy screening were low risk or testing was declined. We recommend a third-trimester ultrasound examination to evaluate growth and consideration of weekly antenatal fetal surveillance beginning at 36 0/7 weeks of gestation (GRADE 1C); (12) for fetuses with isolated urinary tract dilation A1, we recommend an ultrasound examination at ≥32 weeks of gestation to determine if postnatal pediatric urology or nephrology follow-up is needed. For fetuses with urinary tract dilation A2-3, we recommend an individualized follow-up ultrasound assessment with planned postnatal follow-up (GRADE 1C); (13) for fetuses with isolated shortened humerus, femur, or both, we recommend a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C). [ABSTRACT FROM AUTHOR]

Background: To examine disparities by maternal place of birth in the opportunity to make an informed choice about Down syndrome screening, in France, where the national guidelines recommend that physicians offer it to all pregnant women.Methods: We used population-based data from the nationally representative French Perinatal Surveys in 2010 and 2016 (N=24,644 women) to analyze the opportunity for an informed choice for prenatal screening, measured by a composite indicator.Results: Among the 24 644 women in the study, 20 612 (83.6%) were born in France, 861 (3.5%) elsewhere in Europe, 1550 (6.3%) in North Africa, and 960 (3.9%) in sub-Saharan Africa. The probability of screening was lower for women born outside France. After adjustment for survey year, maternal age, parity, education level, and the maternity unit's level of perinatal care, women born outside France had the opportunity to make an informed choice less often than women born in France. This association remained essentially the same even after excluding women without adequate prenatal care.Conclusions: Women born outside France, including those with adequate prenatal care, had less opportunity than women born in France to make an informed choice about prenatal screening for Down syndrome. [ABSTRACT FROM AUTHOR]

Background/aim: Although cutting edge procedures such as cell-free fetal DNA isolation from maternal blood are now available, invasive prenatal tests are still being used extensively for prenatal diagnosis. The study aims to evaluate the demographic data, indications, and cytogenetic results of 9297 results of patients who underwent prenatal invasive testing for genetic analysis that were referred for the last 20 years in a University Medical Genetics Center. Materials and methods: The records of 8363 amniocenteses, 626 chorionic villus, and 308 cordocenteses samples were retrospectively evaluated and analyzed regarding referral reasons, indications and their cytogenetic results. The total numbers and the percentages of each group were recorded; Chi-square and logistic regression analyses were performed to give the statistical likelihood of different events. Results: The number of referrals decreased significantly after 2009. Risk of having trisomy 21 as well as trisomy 13 and 18 significantly increased in parallel with advanced maternal age. When the 21–25 age group was compared to the older age groups in terms of having a trisomy 21 pregnancy, the risk doubled in the 36–40, 5 times higher in 41–45 and 10-fold in 46–50 age groups. No significant linear correlation between maternal serum screening test results and trisomy 21 was found, however the difference between the pregnancies whom cut-off value above and below 1/250 in maternal serum screening test were significant. Conclusion: These data have provided useful information on the frequency of referrals to the reference genetics department, and the feasibility of genetic services. By reviewing the indications and their corresponding results, we can offer invaluable insights that will be useful in genetic counseling and also in the development of more effective genetic strategies. [ABSTRACT FROM AUTHOR]

We summarized our five-year chorionic villus sampling (CVS) experience with indications, detected chromosomal abnormalities and pregnancy outcomes. Materials and Methods: This retrospective study examined 552 patients underwent CVS for prenatal diagnosis between 2014 and 2018. Results: The most frequent patients undergoing CVS indications were abnormal aneuploidy screening results, increased nuchal translucency, and cystic hygroma/edema. Of 552 CVS, 385 were normal, 141 abnormal. Eight were contaminated with maternal cells, 4 were mosaics, in 12 the culture failed, and in 2 there was inadequate sampling. The most frequent chromosomal abnormalities were trisomy 21, trisomy 18 and 45,X. Of 246 followed pregnancies, there were 165 live-births (67,1%), 58 pregnancy terminations (23,6%), and 23 pregnancy losses (9,3%). There were 5 procedure-related losses (2%), 3 of which were chromosomally normal. Conclusion: Although significant advances have been made in noninvasive methods such as NIPT, CVS is still a reliable technique for cytogenetic diagnosis in early gestation. [ABSTRACT FROM AUTHOR]

Background: Chromosomal diseases with chromosomal abnormalities are one of the most common genetic diseases in humans, including abnormal numbers and structural abnormalities. Patau syndrome (also known as trisomy 13), Edward syndrome (also called trisomy 18), and Down syndrome (also known as trisomy 21) are all clinically fatal diseases caused by abnormal numbers of autosomes. However, there is no reliable and effective cure for chromosomal diseases, mainly relying on fast and accurate prenatal diagnosis technology to reduce the rate of birth defects. Methods: Fluorescent-labeled primers were designed and then used in fluorescence quantitative polymerase chain reaction (FQ-PCR) composite amplification, capillary electrophoresis typing, and gene fragment analysis technology to detect 64 amniotic fluid samples, which were indicated high risks of trisomy 18 and 21 by non-invasive prenatal diagnostic technology (NIPT). The results are compared with the results of karyotype analysis and chromosome copy variations (CNVs). Results: Sixty-four samples were determined by FQ-PCR technology with the help of short tandem repeat (STR) regarded as molecular marker (STR-FQ-PCR), the result showed 61 cases of chromosomal aneuploidy were positive, including 14 cases of Edward syndrome and 47 cases of Down syndrome. A total of 460 STR locus genotypes were detected, containing 84 STR locus genotypes of Edward syndrome and 376 STR locus genotypes of Down syndrome. Chromosome karyotype analysis showed that the detected samples were all chromosomal aneuploidy. Among them were 15 cases of trisomy 18, including 14 cases of homozygous type and 1 case of chimeric type, 49 cases of trisomy 21, consisting of 47 cases homozygous type and 2 cases chimeric type. Sixty-two cases of chromosomal aneuploidy were detected by CNVs with 14 cases of trisomy 18 and 48 cases of trisomy 21. Conclusions: The detectable rate of STR-FQ-PCR technology is 95.31% while the karyotype analysis is the highest with 100%. For non-chimera and non-structural abnormal samples, the coincidence rate of results between STRFQ-PCR technology and karyotype analysis was 100%. All above manifested the application of multiple STR loci for rapid diagnosis of Down syndrome and Edward syndrome has high clinical value. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore the value of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal isolated nasal bone absence (INBA) or isolated nasal bone hypoplasia (INBH). We hope to provide additional relevant information for clinical counseling. Patients and Methods: From November 1, 2018, to March 1, 2020, 55 pregnant women with isolated nasal bone dysplasia were admitted to the Changzhou Maternity and Child Health Care Hospital. Based on the degree of abnormality, the patients were divided into two groups: INBA and INBH. CMA was performed on all patients. The clinical data and prenatal genetic diagnoses of the two groups were retrospectively analyzed. According to the requirements of WES for samples, 12 cases with negative CMA results were selected for the WES test. Results: A total of 55 cases with INBA or INBH met the inclusion criteria. In 35INBA fetuses, there was one case of trisomy 21 and one case of 10q11.22 deletion (5.7Mb), and the abnormality rate was 5.71% (2/35). Compared with INBA fetuses, the abnormality rate was increased in the fetuses with INBH [15.00% (3/20)] (15.00% vs 5.71%); there was one case of 1q21.1 duplication (1.3Mb), one case of Xp22.31 duplication (1.67Mb), and one case of 4p deletion (7.6Mb). In a later retrospective study, two pathogenic variants were identified in two cases after the WES test; the abnormality rate was 16.67% (2/12), which involved RUNX2 and CDH4 genes, respectively. Conclusion: A preliminary study confirmed that molecular prenatal diagnosis should be performed in fetuses with INBA or INBH. CMA followed by WES is an effective method. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the accuracy of Z-scores of noninvasive prenatal screening (NIPS) in predicting 21, 18 trisomy, and X chromosome aneuploidy. Methods: A total of 39,310 prenatal women were recruited for NIPS from September 2015 to September 2020. Interventional prenatal diagnosis was applied to verify the diagnosis of NIPS-positive results. Logistic regression analysis was employed to relate the Z-scores to the positive predictive value (PPV) of NIPS-positive results. Using receiver operating characteristic (ROC) curves, we calculated the optimal cutoff value of Z-scores to predict fetal chromosome aneuploidy. According to the cutoff value, NIPS-positive results were divided into the medium Z-value (MZ) and high Z-value (HZ) groups, and PPV was calculated to access the accuracy of Z-scores. Results: A total of 288 effective values of Z-scores were used as the final data set. The logistics regression analysis revealed that Z-scores were significantly associated with true-positive results for 21 trisomy (T21) and 18 trisomy (T18) (P < 0.05), whereas the same was not observed for X chromosome aneuploids (P > 0.05). The optimal cutoff value of the Z-score for T21, T18, XO, XXX, and XXY indicated by ROC curve analysis were 5.79, 6.05, −9.56, 5.89, and 4.47, and the area under the curve (AUC) were 0.89, 0.80, 0.48, 0.42, and 0.45, respectively. PPV in the HZ group was higher than that in the MZ group, and the application of the cutoff value reduced the false discovery rate (FDR), which was only 2.9% in the HZ group compared with 61.1% in the MZ group for T21 and T18. The difference in total PPV between the MZ and HZ groups for X chromosome aneuploids was statistically significant. Moreover, the PPV for XXX and XXY seemed to increase with Z-scores but not for XO. Conclusion: The Z-score is helpful for the accurate judgment of NIPS results and for clinical prenatal counseling. Especially for T21 and T18, Z-scores have an excellent clinical association, which is superior to that seen with X chromosome aneuploids. In addition, using Z-scores to judge NIPS results offers a certain reference value for XXX and XXY but not for XO. [ABSTRACT FROM AUTHOR]

Objectives: A classification termed umbilical‐portal‐systemic venous shunt (UPSVS) for an abnormal umbilical vein (UV), portal vein (PV), and ductus venosus (DV) was proposed recently. According to this classification, there are 3 types of UPSVSs: types I, II, and III. Trisomy 21 associated with UV‐PV‐DV anomalies has been described, but the incidence of trisomy 21 in UPSVS cases, the relationship between UPSVS types and trisomy 21, and the pregnancy outcome are poorly documented. This study aimed to address these issues. Methods: All UPSVS cases diagnosed at our department from 2016 to 2019 were retrospectively studied. The English literature describing UV‐PV‐DV anomalies and trisomy 21 from 2000 to 2019 was searched, and the retrieved cases were analyzed. Results: Four of 20 UPSVS cases identified by us also had trisomy 21, with 2 type I and 2 type II UPSVSs. Ultrasound markers of Down syndrome were observed in all 4 cases that underwent termination of pregnancy (TOP). The literature search retrieved 12 reports including 279 patients, with 29 also having trisomy 21, giving a pooled trisomy 21 incidence rate of 10.4%. Of the 29 cases, 16 had type I, and 9 had type II, whereas UPSVS types in 4 were undeterminable, and 22 cases underwent TOP. Conclusions: There is a high incidence of trisomy 21 in UPSVS cases. Trisomy 21 is associated with a type I or II UPSVS. Most cases with the combined defect underwent TOP. These findings may be used to direct prenatal counseling and management of the combined condition. Access the CME test here and search by article title. [ABSTRACT FROM AUTHOR]

Background: Down syndrome is characterized by trisomy 21 or partial duplication of chromosome 21. Extensive studies have focused on the identification of the Down Syndrome Critical Region (DSCR). We aim to provide evidence that duplication of 21q21.1-q21.2 should not be included in the DSCR and it has no clinical consequences on the phenotype. Case presentation: Because serological screening was not performed at the appropriate gestational age, noninvasive prenatal testing (NIPT) analysis was performed for a pregnant woman with normal prenatal examinations at 22 weeks of gestation. The NIPT results revealed a 5.8 Mb maternally inherited duplication of 21q21.1-q21.2. To assess whether the fetus also carried this duplication, ultrasound-guided amniocentesis was conducted, and the result of chromosomal microarray analysis (CMA) with amniotic fluid showed a 6.7 Mb duplication of 21q21.1-q21.2 (ranging from position 18,981,715 to 25,707,009). This partial duplication of 21q21.1-q21.2 in the fetus was maternally inherited. After genetic counseling, the pregnant woman and her family decided to continue the pregnancy. Conclusion: Our case clearly indicates that 21q21.1-q21.2 duplication is not included in the DSCR and most likely has no clinical consequences on phenotype. [ABSTRACT FROM AUTHOR]

Background: Fetoplacental discrepancies occur in approximately 1–2% of analyzed prenatal cases. They are typically due to confined placental mosaicism, where an aberration is observed in the placental cells but not found in the fetal cells. Confined placental mosaicism usually involves aneuploidies and more sparsely structural chromosomal aberrations. To the best of our knowledge, this is the first reported case of a discrepancy in the analyses of chorionic villus sampling and amniocentesis involving two different structural chromosomal aberrations of chromosome 21. Case presentation: We report a 33-year-old woman who was referred for a non-invasive prenatal testing due to an increased risk of trisomy 21 gleaned from a combined ultrasound and blood test. The non-invasive prenatal testing showed an increased risk of trisomy 21 with a normalized coverage signal that did not match the fetal cell-free DNA fraction. Rapid aneuploidy detection performed on uncultured chorionic villi indicated mosaicism for trisomy 21. The follow-up analyses revealed discordant chromosomal aberrations: 46,XY,der(21)t(10;21)(p11.21;q10) in the analysis of the chorionic villus sampling and 46,XY, + 21,der(21;21)(q10;q10) in the analysis of the amniocentesis. Thus, the analyses indicated mosaicism for a cell line containing trisomy 21 and a cell line containing a partially duplicated short arm of chromosome 10 in the chorionic villi and complete trisomy 21 resulting from an isochromosome 21 in the amniotic fluid. The analyses of the lymphocytes and the fibroblasts of the woman were normal. Conclusions: We propose a multiple-step mechanism as a possible theoretical explanation for the formation of these discordant structural chromosomal aberrations in the chorionic villi and amniotic fluid. With this case report, we want to highlight the importance of understanding the possible underlying embryological mechanisms when interpreting results from different prenatal analyses. [ABSTRACT FROM AUTHOR]

Purpose: Noninvasive prenatal testing (NIPT) is a highly sensitive and specific method for detection of fetal chromosomal aneuploidies from maternal plasma. The objective of this study was to determine the performance of a new paired-end sequencing-based NIPT assay in 13,607 pregnancies from a single center in Germany.Methods: Samples from 13,607 pregnant women who previously underwent NIPT were analyzed using VeriSeq NIPT Solution v2 assay for presence of common fetal trisomies and monosomy X. Follow-up to determine clinical truth was carried out.Results: Of the 13,607 cases, 13,509 received a NIPT call resulting in a low study failure rate of 0.72%. There were 188 (1.4%) high-risk calls: 117 trisomy 21, 34 trisomy 18, 23 trisomy 13, one trisomy 21 + 13, and 13 monosomy X. High sensitivities and specificities of ≥ 98.89% were reported for all four aneuploidy conditions. Of the high-risk cases, clinical follow-up data were available for 77.1% (145/188). Clinical follow-up of high-risk calls revealed an overall positive predictive value of 84.8% (potential range 65.4-88.3%). NIPT results were provided for samples across a range of fetal fractions, down to 2% fetal fraction.Conclusion: The VeriSeq NIPT Solution v2 assay detected fetal chromosomal aneuploidies across a range of fetal fractions with high sensitivities and specificities observed based on known clinical outcomes, a high overall PPV, and a low failure rate. [ABSTRACT FROM AUTHOR]

This paper examines women's experiences with decision-making about non-invasive prenatal testing (NIPT). Such tests offer knowledge about chromosomal disorders early in pregnancy, without the risk of miscarriage associated with invasive procedures such as amniocentesis. Based on qualitative interviews with women in Germany who used, or declined, NIPT, we show how some women, who would not consider amniocentesis due to the risk of miscarriage, welcome the knowledge provided by, and the additional agency resulting from, NIPT. For others, declining the offer to "know more" becomes increasingly difficult to articulate. The absence of risk strips women of a "good reason" to justify their decision not to test, thus implicitly challenging their "right not to know." Moreover, NIPT heightens moral dilemmas within relationships with partners, existing children, and sometimes other close relatives. While clinically "non-invasive," we argue that NIPT changes decision-making in an ethically and socially highly significant way. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies.Methods: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort.Results: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies.Conclusion: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations. [ABSTRACT FROM AUTHOR]

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Background: Nowadays several Prenatal Tests for Chromosomal Abnormalities Detection (PTCAD) are available. In those cases in which there is not an Institutional protocol to advise women about the available PTCAD, the choice of which one to undergo is up to the woman and largely depends on her knowledge about them. Therefore, we decided to evaluate, as a primary outcome, knowledge about PTCAD among pregnant women attending our Term Clinic. As a secondary outcome we evaluated the relationship between the patient's knowledge and the subsequently chosen PTCAD. Methods: From August 2017 to August 2018 an anonymous questionnaire with multiple-choice answers was administered to all pregnant women attending our Term antenatal Clinic, a tertiary obstetric unit in Catanzaro (Italy). Results: Three hundred and twenty-five pregnant women were enrolled in the study. We observed that 28.8% of the pregnant women that chose one of the PTCAD, avoided the first trimester combined screening test; among these, 11.4% were in favour of the cell-free foetal DNA test. The latter was erroneously considered diagnostic by 34.3% of the women that had chosen it. Conclusions: This study demonstrated that women's knowledge about PTCAD is poor and that there is a potentially dangerous confusion between the words 'screening' and 'diagnostic'. Informative campaigns about PTCAD and the application of dedicated antenatal counselling appointments should be a health-care priority to avoid unnecessary risks and costs for pregnant women and possible legal issues. [ABSTRACT FROM AUTHOR]

Background: Small supernumerary marker chromosomes (sSMCs) are chromosomal fragments with abnormal structures found in patients with fertility problems and developmental delay. They may be detected in amniotic cell karyotypes. sSMCs are categorized as hereditary or de novo. Here, we describe a case of prenatal de novo 4q11q12 sSMC and its molecular cytogenetic features which had no apparent phenotypic abnormality. Case: The fetus of a 36-yr-old pregnant woman was detected positive for Down's syndrome (trisomy 21) at the 16th wk of gestation. Quantitative fluorescent polymerase chain reaction technique was applied for the rapid detection of numerical aneuploidy of chromosomes X, Y, 13, 18, and 21 microsatellites. Array comparative genomic hybridization (array CGH) technique was also conducted following the karyotype analysis of amniotic cells. The karyotype analysis was also done for the parents. Quantitative fluorescent polymerase chain reaction result revealed a male fetus with a normal chromosomal pattern, while the amniocentesis karyotype analysis identified a male fetus with a marker chromosome (47, XY, +mar), and the sSMC were existing in 100% of amniocyte metaphase spreads. The parents' normal karyotypes indicated that the sSMC was de novo. Array CGH analysis revealed a 6.48-Mb duplication at 4q11q12. Eventually, the parents decided to terminate the pregnancy by legal abortion. Conclusion: Our study highlights the importance of the application of array CGH in combination with karyotype analysis for rapid and precise prenatal diagnosis of partial aneuploidy region. [ABSTRACT FROM AUTHOR]

aimed to evaluate and analyze the results of karyotyping by amniocentesis and next generation sequencing (NGS)-based noninvasive prenatal DNA testing (NIPT) for the prenatal diagnosis of fetal chromosomal disorders. Methods: A total of 2267 high-risk pregnant females with the indications for prenatal diagnosis who met the enrollment criteria between January 2015 and May 2019 at the Affiliated Hospital of Inner Mongolia Medical University were included and underwent NGS-based NIPT in the present study. Amniocentesis, chromosome karyotyping by cell culture, and follow-up of the pregnancy outcomes were also conducted in the NIPT-positive pregnant females to assess the consistency between NIPT and results of karyotyping by amniocentesis. Results: Among the 2267 cases, 29 cases were positive for NIPT, including 10 cases with a high risk of trisomy 21, 2 cases with a high risk of trisomy 18, 2 cases with a high risk of chromosome 13, and 20 cases with sex chromosome abnormalities. All the above NIPT-positive cases underwent amniocentesis, and 20 cases were eventually diagnosed. The sensitivity and specificity of NIPT for the diagnosis of trisomy 21, trisomy 13, and trisomy 18 were 100%, 99.96%, 100%, and 99.96%, 100%, 100%, respectively, and the positive predictive values were 91.67%, 66.67%, and 100%, respectively. Conclusion: NGS of the fetal free DNA from the peripheral blood of pregnant females was an important complement to the prenatal diagnosis of chromosomal disorders represented by fetal chromosome aneuploidy with high sensitivity and specificity. In combination with the traditional karyotyping by amniocentesis, it could improve the diagnostic efficacy for fetal chromosomal disorders. [ABSTRACT FROM AUTHOR]

Background: Echogenic intracardiac focus (EIF) is a common ultrasound finding during pregnancy. However, the correlation between fetal EIF and cardiac abnormality remains in dispute until now. The study aimed to examine the association of fetal EIF with chromosomal abnormality by means of chromosomal microarray analysis (CMA). Materials and Methods: A total of 192 pregnant women with fetal EIF undergoing amniocentesis or umbilical cord blood puncture were recruited and assigned into groups A (8 cases with isolated EIF alone), B (75 cases with EIF and other cardiac malformations) and C (109 cases with EIF and extracardiac malformations). All fetuses underwent karyotyping analysis and CMA simultaneously. The detection of chromosomal abnormality and copy number variations (CNVs) were compared. Results: Chromosomal karyotyping identified 5 fetuses with chromosomal abnormality, including 3 cases with trisomy 21, one fetus with Turner's syndrome, and one fetus with chromosome 8 mosaicism, while CMA detected 6 additional fetuses with CNVs, including 2 fetuses with pathogenic CNVs and 4 fetuses with variants of uncertain significance (VOUS). There was no significant difference among groups A (0), B (5.33%) and C (6.42%) in terms of the prevalence of chromosomal abnormality (P> 0.05). Among the 4 fetuses with VOUS, pregnancy continued in 2 fetuses, and pregnancy was terminated in other 2 fetuses. Conclusion: An isolated EIF may not correlate with chromosomal abnormality. However, CMA is recommended in fetuses with CMA complicated by other abnormal cardiac ultrasound findings, which facilitates the prediction of fetal outcomes during the genetic counseling and precision assessment of prognosis. [ABSTRACT FROM AUTHOR]

Prenatal testing and diagnosis are gaining a strong foothold in a progressively developing country like India, and an estimated boom in the market of noninvasive prenatal testing is predicted by the year 2024. Having said this, every technique needs an adequate amount of supplementation to increase its worth and that is where genetic counseling proves to be indispensable. Postdiagnosis, the women classified as high-risk individuals likely to give birth to infants inflicted with congenital and structural anomalies are appropriately counseled regarding the clinical aspects of the disease, life expectancy associated with the same, and the consequences associated with the decision to go ahead and conceive the child. Genetic counseling is majorly done for Down syndrome as the other aneuploidies have a highly reduced life expectancy. Although there are a variety of techniques available for testing various chromosomal anomalies, information regarding the appropriate time of the test and emphasis on pre- and posttest counseling is usually not supplied to primary physicians. A considerable amount of confusion dominates the decision of which test should be employed for testing of which anomaly as an array of rather efficient techniques has been identified. Furthermore, there is no nation-wide consensus of the timing and nature of these screening protocols. Moreover, ambiguous guidelines along with an impending lacuna in terms of awareness have led to India being at the backseat of the era that has ushered in tons of technological advancement in this field.

Noninvasive prenatal screening using cell-free DNA involves analysis of a sample of maternal blood for DNA fragments of fetal chromosomes from the fetal-placental unit to detect common chromosome abnormalities, trisomy 21, trisomy 13, trisomy 18, and sex chromosomes as early as 10 weeks' gestation when the fetal fraction is usually more than 4%. It is the most sensitive and specific prenatal screening option for these conditions. Because it is a screening test, false-positive and false-negative results can occur. Positive screen results necessitate further evaluation for diagnosis to confirm a medical condition, before critical decisions regarding pregnancy are made. Professional organizations provide clinical recommendations to providers regarding prescreen and postscreen counseling and management of results. [ABSTRACT FROM AUTHOR]

Introduction Fetal nasal bone hypoplasia has been proven to be a strong marker for trisomy 21 during second trimester ultrasonography. Rather than evaluating the nasal bone hypoplasia according to the nomograms, it may be possible to evaluate it with a more practical and specific method. Material and methods Retrospectively collected data were provided from the saved and stored patient data between 2012 and 2017. Nasal bone length and nasal tip length were measured and the ratio was calculated. The ratio ≤ 1/3 was defined as the threshold ratio for the definition of the marker. Nasal bone nasal tip length (NB/NL) ratio values were compared among groups with trisomy 21 and euploid fetuses. Results A total of 59 fetuses had trisomy 21 and 2304 euploid fetuses were included in the study. The ratio of nasal bone to nasal tip length was 1/3 and below in 21/59 (35.5%) of fetuses with trisomy 21 whereas this ratio was 31/2304 (1.3%) in euploid fetuses. The difference was statistically significant (p < 0.001). Sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of nasal bone/nasal tip ratio ≤ 1/3 were 35.5%, 98.6%, 26.4 and 0.6 for Down syndrome, respectively. Conclusions This study suggested that the nasal bone to nasal tip length ratio may be a new promising and practical sonographic marker in the second trimester genetic sonography. Although its sensitivity is not high, it seems to be more practical and specific than the evaluation of fetal nasal bone length.

Background: In Europe, about 76% of cases of chromosomal anomalies are prenatally diagnosed. Prenatal diagnosis allows more efficient planning of postnatal treatment and helps parents for an informed decision about the continuation of pregnancy. The main aim of this study was to evaluate whether the sociodemographic maternal characteristics affect the probability of prenatal diagnosis of chromosomal anomalies.Methods: Cases of chromosomal anomalies in the period 2005–2017 came from the population-based registry of congenital anomalies of Tuscany (Italy). Differences in the proportion of cases prenatally diagnosed were investigated through the following maternal characteristics: education, geographic origin and occupation. The association between cases of termination of pregnancy after prenatal diagnosis and maternal characteristics was also analysed. Odds Ratios (OR) adjusted by maternal age were calculated using logistic regression models. Results were provided for all cases of chromosomal anomalies and for Down syndrome cases.Results: A total of 1,419 cases were included in the study. Cases prenatally diagnosed were 1,186 (83.6%). We observed a higher proportion of cases not prenatally diagnosed among cases with low maternal education compared to those with high maternal education (OR = 2.16, p < 0.001) and in women from high migratory outflow countries, compared to the Italian ones (OR = 2.85, p < 0.001). For prenatally diagnosed Down syndrome cases, we observed a higher proportion of termination of pregnancy for women with low education level (OR = 4.36, p = 0.023).Conclusions: In our study evidence of differences in the probability of prenatal diagnosis of chromosomal anomalies associated with maternal education and geographic origin was found. Population-based studies investigating sociodemographic disparities can provide essential information for targeted public health programs. Further studies are recommended to monitor the impact of the increasing availability of non-invasive screening tests.

Background: This paper describes the clinical practice and performance of cell-free DNA sequencing-based non-invasive prenatal testing (NIPT) as a screening method for fetal trisomy 21, 18, and 13 (T21, T18, and T13) and sex chromosome aneuploidies (SCA) in a general Italian pregnancy population. Methods: The AMES-accredited laboratory offers NIPT in maternal blood as a screening test for fetal T21, T18, T13 and SCA. Samples were sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay. Results: A retrospective analysis was performed on 36,456 consecutive maternal blood samples, including 35,650 singleton pregnancies, 800 twin pregnancies, and 6 triplet pregnancies. Samples were tested between April 2017 and September 2019. The cohort included 46% elevated-risk and 54% low-risk patients. A result indicative of a classic trisomy was found in 356 (1%) of singleton or twin samples: 254 T21, 69 T18, and 33 T13. In addition, 145 results (0.4%) were indicative of a SCA. Of the combined 501 screen-positive cases, 484 had confirmatory diagnostic testing. NIPT results were confirmed in 99.2% (247/249) of T21 cases, 91.2% (62/68) of T18 cases, 84.4% (27/32) of T13 cases, and 86.7% (117/135) of SCA cases. In the 35,955 cases reported as unaffected by a classic trisomy or SCA, no false negative cases were reported. Assuming that false negative results would be reported, the sensitivity of NIPT was 100.00% for T21 (95% Cl 98.47–100.0), T18 (95% Cl 94.17–100.0), and T13 (95% Cl 87.54–100.0). The specificities were 99.99% (95% Cl 99.98–100.0), 99.98% (95% Cl 99.96–100.0), 99.99% (95% Cl 99.97–100.0), and 99.95% (95% Cl 99.92–99.97) for T21, T18, T13, and SCA, respectively. Conclusion: This retrospective analysis of a large cohort of consecutive patients who had whole-genome sequencing-based NIPT for classic trisomies and SCA shows excellent detection rates and low false positive rates. [ABSTRACT FROM AUTHOR]

This study presents a retrospective data analysis of 101 postnatally detected cases of Down syndrome, routinely diagnosed among 1879 postnatal investigations performed during a 15-year period (2005-2020) at a single tertiary centre. All patients with features of Down syndrome were examined at the Department of Paediatrics, Osijek University Hospital Centre. Karyotyping was performed at the Laboratory of Medical Genetics, Faculty of Medicine in Osijek. Among 101 Down syndrome patients, 55% patients were male and 45% were female patients. Trisomy 21 as the most common karyotype was found in 95%, Robertsonian translocation in 4% and mosaic form in 1% of Down syndrome patients. The average age of the mothers was 33 years. Congenital heart defects were present in 38/89 (42.7%) patients. There was no marked decrease in the prevalence of live birth Down syndrome in eastern Croatia over the 15-year period. The usage of prenatal diagnosis was low, so women's, as well as physicians' knowledge and attitudes towards the prenatal diagnosis of Down syndrome should be evaluated. [ABSTRACT FROM AUTHOR]

Aims: To compare the screening capability of ultrasonography in detecting trisomy 13 (T13) using a multiparameter sonographic protocol (NT+) with a classical combined screening test (CST) protocol.Methods: The project was a prospective, multicenter study based on a nonselected mixed-risk population of women referred for a first-trimester screening examination. Each subject was offered a choice between either the gold standard, traditional combined screening test (CSG arm) or the ultrasound-based screening protocol (USG arm). General and MA-based screening performances were checked.Results: The study population comprised 20,887 pregnancies: 12,933 in the CSG arm, including 27 cases of T13, and 7954 in the USG arm, including 30 cases of T13. The DR for T13 was higher in the CSG arm than in the USG arm for all tested cutoff points: 1/50 (88.5 versus 63.3%, respectively), 1/100 (88.5 versus 70%, respectively) and 1/300 (92.3 versus 83.3%, respectively). Using the ROC curves for fixed FPRs of 3 and 5%, the T13 detection rate in our study reached 90 and 93%, respectively, in the USG arm and 92 and 96%, respectively, in the CSG arm. MA influenced the T13 screening performance in the USG arm and reduced the DR in patients <31 years. Such influence was not detected in the CSG arm.Conclusions: Classic CST was more effective in detecting T13 than the ultrasound-only approach. However, the recommended cutoff of 1/50 showed unsatisfactory results for both traditional CST and the multiparameter sonographic test we proposed. [ABSTRACT FROM AUTHOR]

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Introduction: Austere clinical settings, including remote military installations, face unique challenges in screening pregnant women for aneuploidy. The objective of this study was to compare the direct and indirect prenatal costs of traditional 2-part serum-based screening to cell-free DNA (cfDNA) for detection of trisomies 18 and 21 for a military treatment facility with limited in-house perinatal resources.Materials and Methods: We identified Naval Hospital Guantanamo Bay as a surrogate for an austere clinical environment. A prenatal cost of care analysis incorporating direct and indirect expenses was performed to compare the 2 aneuploidy screening strategies for a theoretical cohort of 100 patients for detection of trisomies 18 and 21. The baseline aneuploidy uptake rate was determined using a historical cohort. Test performance characteristics were obtained from the contracting laboratory. Aneuploidy rates and costs were calculated using previously published data.Results: Assuming a baseline screen uptake rate of 87%, initial screening using the traditional approach would directly cost $8,285.01 versus $44,140.32 with cfDNA. Considering indirect costs such as travel, consultative services, evaluation and follow-up testing of an abnormal screen result, and lost productivity, the cost difference narrows to $14,458.25 over a 5- to 6-year period. Cost equivalence is achieved when cfDNA is priced at $341.17 per test.Conclusion: Cell-free DNA as an initial screening strategy offers enhanced detection rates for trisomies 18 and 21 but remains more costly than traditional screening when incorporating direct and indirect expenses. In a low volume setting with limited resources, the added cost may be justified given the implications of unrecognized aneuploidy. [ABSTRACT FROM AUTHOR]

Aim: To investigate the epidemiology of chromosomal abnormalities (CA) in fetuses of all pregnancies based on a provincial‐wide birth defects‐monitoring system, which could provide scientific basis for making relatively policy and research. Methods: Chromosomal abnormalities cases were collected from all hospitals in Hunan Province, China, between 2016 and 2019. The prevalence of CAs was calculated to examine associations among infant sex, maternal age and region. The rates of prenatal diagnosis and termination of pregnancy (TOP) involving CA or associated anomalies were calculated as rates or proportions. Results: From 2016 to 2019, a total of 2 883 890 perinatal infants (28 weeks of gestation to postpartum 7 days) underwent prenatal screening and diagnostic tests, and 3181 fetuses were diagnosed as CA, with the prevalence of 11.03/10 000. The average prevalence of CAs was higher for male than female fetuses (11.33/10 000 vs 10.06/10 000) (OR = 1.13, 95% CI: 1.05–1.21), which was higher in urban areas than rural areas (23.03/10 000 vs 7.13/10 000) (OR = 3.23, 95% CI: 3.02–3.47), and the prevalence increased linearly with maternal age (Xtrend2 = 1821.844, P = 0.000). Among the fetuses with CAs, 3097 (97.36%) were diagnosed prenatally, and 3046 (98.35%) underwent TOP. The majority of CA were numerical abnormalities (90.18%). The main types of numerical autosomal abnormalities were trisomy 21 (6.69/10 000, 59.57%), trisomy 18 (1.13/10 000, 10.04%) and trisomy 13 (0.21/10 000, 1.88%). The main types of numerical gonosomal abnormalities were Klinefelter syndrome (0.68/10 000, 6.02%), Turner syndrome (0.49/10 000, 4.39%), Triple X syndrome (0.26/10 000, 2.29%) and 47,XYY syndrome (0.21/10 000, 1.91%). The three associated anomalies with the highest proportions were congenital heart defects (CHD) (41.06%), cleft palate or/and cleft lip (10.89%) and congenital talipes equinovarus (8.94%). Conclusion: The prevalence of CA was lower than that reported. Chromosome detection should be further promoted including test contest and coverage, especially for urban areas, older mothers and fetuses with CHD, cleft palate or/and cleft lip or congenital talipes equinovarus. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing (NIPT) is a genomic technology used to predict the chance of a foetus having a genetic condition. Despite the immediacy of this technology's integration into clinical practice, there is a dearth of evidence outlining how both patients and professionals experience NIPT on the ground. In this article, we draw upon our collective empirical research—specifically on earlier screening technologies (BKR), Down syndrome screening (GT), genetic screening/testing (JL) and NIPT (HS)—to outline the most pressing and often controversial issues which, we argue, remain unresolved and vital to consider regarding NIPT. We begin with a brief introduction to NIPT as a prenatal technology and the bodies of literature which unpack its 'social life'. In what follows, BKR discusses NIPT within the context of her research on 'the tentative pregnancy' and diagnostic testing in the USA. In the following sections, GT, HS and JL identify different, but related, concerns with respect to NIPT, particularly around routinisation, commercialisation, choice, abortion, and configurations of disability and 'normalcy'. [ABSTRACT FROM AUTHOR]

Background: Non-invasive prenatal testing (NIPT) for aneuploidy in pregnant women screening has been recently established in Saudi Arabia. We aim from this study to report our experience in the implementation of this new technology in clinical practice and to assess factors influencing cell-free fetal (cffDNA) fraction and successful NIPT reporting. Methods: In total, 200 pregnant women were subjected to the NIPT test using standard methods. Next-generation sequencing (NGS) was used to analyze cffDNA in maternal plasma. Results: Out of the 200 NIPT cases, the average age of pregnant women was 35 ± 6 years (range: 21–48 years). The average cffDNA fraction of reported cases was 13.72% (range: 3–31%). Out of these 200 cases, 187 (93.5%) were at low risk, while 13 (6.5%) cases revealed high risk for aneuploidy. Among these chromosomal abnormalities, 7 (3.5%) cases of Down's syndrome, 5 (2.5%) Edwards' Syndrome, and only 1 case of (0.5%) Patau's syndrome was observed. Out of the 13 high-risk cases, 2 (15.3%) were found in women below the age of 30. Conclusion: This is the first study reporting the successful implementation of an in-house NIPT screening service in Saudi Arabia. Our data showed high accuracy and sensitivity to detect high-risk cases indicating the usefulness of such a technique as an alternative to invasive testing and (hopefully) will change the common screening practice for pregnant women in Saudi Arabia. [ABSTRACT FROM AUTHOR]

This study aims to present the termination of pregnancy (TOP) rates and elucidate the decision-making process following a prenatal diagnosis of Trisomy 21 in Turkey. This retrospective single-center study was conducted with 146 pregnant women between January 2016 and December 2019 in a tertiary hospital. Data on maternal characteristics, sonographic findings, indications for chromosome analysis, and educational, religious, and economic factors that can influence the parental decision process were collected. The TOP rate of Down syndrome (DS) in our center was 78.8%. We concluded that maternal age, earlier diagnosis, indication for chromosome analysis, and previous pregnancies had no effect on the TOP decision. On the other hand, not having a minor or a major sonographic sign, employed mothers, middle- and high-income families, and families having a secondary or higher education tended to terminate the pregnancy affected by DS at statistically higher rates. There are many studies worldwide investigating the TOP preferences for DS. However, there is limited data about TOP rates and influential factors affecting the decision-making process in Muslim countries. This study contributes by clarifying the factors in the decision-making process and elucidating perspectives about TOP in a Muslim country with a unique status: Turkey. [ABSTRACT FROM AUTHOR]

Limited knowledge exists about how frequently newborns with Down syndrome receive a prenatal diagnosis, require intensive care, and what surgical and medical factors are contributory. A retrospective cohort study was performed for patients with a diagnosis of Down syndrome born in 2013 and 2014 who sought care at Cincinnati Children's Hospital Medical Center during the first year of life. Data were extracted from the electronic medical record through the first year of life including need for intensive care as a newborn, prenatal diagnosis, and medical and surgical complications. Of the 129 patients in the study, 65% required intensive care as newborns. The presence of a structural abnormality that required surgical correction in the neonatal period and certain types of congenital heart disease not requiring surgical intervention in the neonatal period were positively associated with the need for intensive care. A minority of infants, 8%, had a confirmed prenatal diagnosis. A majority of newborns with Down syndrome required intensive care following birth while a minority had any concern for the diagnosis prenatally. Improving prenatal diagnostic rates would allow for better prenatal counseling and delivery planning, while targeting therapeutic interventions for this population is needed to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Trisomy 19q is a recognizable syndrome and associated with a wide spectrum of clinical phenotypes in clinic. The purpose of this study was to explore the prenatal phenotypes of 19q13.42 duplication, which was rarely reported in clinic. Case presentation: Three pregnant women presenting diverse indications for prenatal diagnosis accepted amniocentesis: increased nuchal translucency and fetal pyelic separation (case 2) and high risk of maternal serum screening for Down syndrome (case 1 and case 3). Case 1 and case 2 shared similar duplicated locus in the region of 19q13.42, encompassing part NLRP12 gene. The latter inherited the chromosomal duplication from the mother with normal phenotypes. Case 3 carried a 1.445 Mb duplication in the 19q13.42q13.43 region. It was proposed that evolutionary duplication of NLRP12 gene could have a causative role in autoinflammatory diseases development. The genotype–phenotype correlation depends mainly on the duplicated size and functional genes involved, which is still yet to be determined. All pregnant women chose to continue the pregnancy and delivered healthy children with no apparent abnormalities. Conclusions: The 19q13.42 microduplications in our study were the smallest fragments compared to previous literature. Our findings enriched the prenatal phenotypes for this chromosomal microscopic imbalance. It was proposed that long term follow up analysis should be guaranteed till adulthood to determine whether there will be other emerging clinical symptoms and developmental-behavioral disorders for such carriers. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal testing (NIPT) promises to enhance women's reproductive autonomy by providing genetic information about the fetus, especially in the detection of genetic impairments like Down syndrome (DS). In practice, however, NIPT provides opportunities for intensified manipulation and control over women's reproductive decisions. Applying Miranda Fricker's concept of epistemic injustice to prenatal screening, this article analyzes how medical professionals impair reproductive decision-making by perpetuating testimonial injustice. They do so by discrediting positive parental testimony about what it is like to raise a child with DS. We argue that this testimonial injustice constitutes a twofold harm: (1) people with DS and their family members who claim that parenting a child with DS may be a rewarding and joyous experience are harmed when they are systematically silenced, disbelieved, and/or denied epistemic credibility by medical professionals, and (2) pregnant women are harmed since they might make poorly informed choices without access to all relevant information. The broader implication of the analysis is that epistemic justice is a precondition of reproductive autonomy. We conclude by calling for federal oversight of the acquisition and dissemination of information that prospective parents receive following a positive diagnosis of DS to ensure that it is comprehensive and up to date. [ABSTRACT FROM AUTHOR]

Objective: Maternal characteristics and neonatal outcomes associated with cell-free DNA (cfDNA) results were analysed retrospectively to assess the details of false-positive and false-negative results after initial blood sampling in non-invasive prenatal testing (NIPT).Study Design: A multicentre retrospective study was performed for women undergoing NIPT who received discordant cfDNA results between April 2013 and March 2018. The NIPT data obtained using massive parallel sequencing were studied in terms of maternal background, fetal fraction, z-scores, invasive procedure results and neonatal outcomes after birth.Results: Of the 56,545 women who participated in this study, 54 false-positive (0.095 %) and three false-negative (0.006 %) cases were found. Seven of the 54 false-positive cases (13.0 %) had vanishing twin on ultrasonography. Among the 18 false-positive cases of trisomy 18, confined placental mosaicism (CPM) was confirmed in three cases (16.7 %), while CPM was present in one of the three false-negative cases of trisomy 21.Conclusion: These data suggest that the incidence of women with false-positive or false-negative results is relatively low, that such false results can often be explained, and that vanishing twin and CPM are potential causes of NIPT failure. Genetic counselling with regard to false results is important for clients prior to undergoing NIPT. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this survey is to evaluate the knowledge of Chinese pregnant women about fetal chromosomal aneuploidy and microdeletion and microduplication syndromes, and Non-invasive prenatal testing (NIPT).Study Design: Written questionnaires were distributed to pregnant women who visited the fetal medicine clinic of the third affiliated hospital of Guangzhou medical university. A total of 330 questionnaires were given. Twenty-two questionnaires with incomplete information were excluded from further analysis. The remaining 308 cases were incorporated into the final analysis. Data were analyzed using IBM SPSS Statistics 26. Comparisons between categorical variables were tested by the use of crosstabs and χ 2 test.Results: Among pregnant women, the recognition of Down syndrome was the highest (93.5 %), followed by maternal serum screening (74.0 %) and NIPT (69.2 %) for chromosomal aneuploidy. The awareness rates of chromosomal microdeletions and microduplications (18.2 %) and monogenic disorders (13.3 %) were the lowest. There were no significant differences in age, education, and conception way between pregnant women (P > 0.05). When asked the opinion on increasing the testing range of NIPT, more than 50 % of pregnant women chose to follow the provider's advice.Conclusion: More than half of pregnant women lacked knowledge of screening methods for fetal chromosomal abnormalities. Less than 20 % of pregnant women knew microdeletion microduplication syndromes. To enhance the understanding of chromosomal abnormalities can ensure that women can actively choose tests rather than passively agreeing to their provider's recommendations so as to avoid missing the optimal prenatal screening time. [ABSTRACT FROM AUTHOR]

Objective: To investigate factors associated with fetal fraction and to develop a new predictive method for low fetal fraction before noninvasive prenatal testing. Methods: The study was a retrospective cohort analysis based on the results of noninvasive prenatal testing, complete blood count, thyroxin test, and Down's syndrome screening during the first or second trimester in 14,043 pregnant women. Random forests algorithm was applied to predict the low fetal fraction status (fetal fraction < 4%) through individual information and laboratory records. The performance of the model was evaluated and compared to predictions using maternal weight. Results: Of 14,043 cases, maternal weight, red blood cell, hemoglobin, and free T3 were significantly negatively correlated with fetal fraction while gestation age, free T4, pregnancy-associated plasma protein-A, alpha-fetoprotein, unconjugated estriol, and β-human chorionic gonadotropin were significantly positively correlated with fetal fraction. Compared to predictions using maternal weight as an isolated parameter, the model had a higher area under the curve of receiver operating characteristic and overall accuracy. Conclusions: The comprehensive predictive method based on combined multiple factors was more effective than a single-factor model in low fetal fraction status prediction. This method can provide more pretest quality control for noninvasive prenatal testing. [ABSTRACT FROM AUTHOR]

Clinical performance of the Momguard non-invasive prenatal test (NIPT) was evaluated in a cohort of Korean pregnant women. The foetal trisomies 21, 18 and 13 (T21, T18 and T13) were screened by low-coverage massive parallel sequencing in the maternal blood. Among the 1011 confirmed samples, 32 cases (3.2%) had positive NIPT results. Of these positive cases, 20 cases of T21, all cases of T18 and two cases of T13 had concordant karyotype findings. Only one case out of the remaining 979 negative NIPT samples showed a false negative result. The overall sensitivity and specificity of Momguard to detect the three chromosomal aneuploidies were 96.8% and 99.8%, respectively. Momguard is a clinically useful tool for the detection of T21, T18 and T13 in singleton pregnancy. However, as other NIPT tests, it carries the risk of false positive and false negative results. Hence, the genetic counsellors should provide these limitations to the examinees.Impact StatementWhat is already known on this subject? The NIPT approach using massive parallel sequencing (MPS) showed high sensitivity and specificity in various clinical studies. These results are based on analysis systems using their own bioinformatics algorithms.What the results of this study add? When this NIPT technology was introduced in Korea, the first biological specimens collected in Korea were transported overseas for processing in overseas laboratories and analysed by other country's analysis methods. We needed our own NIPT algorithm and developed Momguard NIPT for the first time in Korea. This study attempted to evaluate this Momguard NIPT protocol prospectively in a large number of samples obtained from three Korean hospitals.What the implications are of these findings for clinical practice and/or further research? The overall sensitivity and specificity to identify T13, T18 and T21 were 96.8% and 99.8%, respectively. These accuracy values were comparable to that of other studies. From this study, we found that Momguard is a clinically useful tool for the detection of three chromosomal aneuploidies. However, as other NIPT tests, it carries the risk of false positive and false negative results. Hence, the genetic counsellors should provide these limitations to the examinees. [ABSTRACT FROM AUTHOR]

Down syndrome screening has been available within clinical practice for over 50 years within which time significant innovation and exciting new advances have improved the accuracy, safety, and choice for women who are considering antenatal screening for Down syndrome. The UK National Screening Committee is responsible for setting the national standards regarding screening and it has steadily and consistently directed and facilitated an increase in the detection rate whilst minimising the screen positive rate. This has reduced the number of false positive results and consequently the number of invasive diagnostic procedures and their related miscarriages. Non-invasive pre-natal testing (NIPT) using cell free DNA is a rapidly evolving field and it will soon be incorporated into the existing NHS antenatal screening programme for aneuploidy. It will be offered to women who receive a 'high risk' result following current screening methods (combined test or quadruple test), and will further reduce the number of invasive tests performed, whilst maintaining current detection rates. [ABSTRACT FROM AUTHOR]

Abstract Background Norway’s liberal abortion law allows for abortion on social indications, yet access to screening for fetal abnormalities is restricted. Norwegian regulation of, and public discourse about prenatal screening and diagnosis has been exceptional. In this study, we wanted to investigate whether the exceptional regulation is mirrored in public attitudes. Method An electronic questionnaire with 11 propositions about prenatal screening and diagnosis was completed by 1617 Norwegian adults (response rate 8.5%). Results A majority of respondents supports increased access to prenatal screening with ultrasound (60%) and/or full genome sequencing of fetal DNA (55%) available for all pregnant women. Significant minorities indicate, however, that a public offer of prenatal screening for all pregnant women would signal that people with Down syndrome are unwanted (46%) or could be criticized for contributing to a ‘sorting society’ (48%). Conclusions Results indicate deeper ambivalences and a cultural sensitivity to the ethical challenges of prenatal screening and subsequent abortions. The specific diagnosis of Down syndrome and the fear of becoming a ‘sorting society’ which sorts human life due to diagnoses, appear to play prominent roles in citizen deliberations. The low response rate means that a non-response bias cannot be excluded, yet reasons why results are still likely to be of value are discussed.

Abstract Background Tetrasomy 21 is a very rare aneuploidy which could clinically resemble a Down syndrome. It was most often described in its partial form than complete. We report the prenatal, pathological and genetic characteristics of a fetus with mosaic complete tetrasomy 21. This is the second well‐documented description of a complete tetrasomy 21 in the literature. Methods Prenatal and fetal pathological examinations, cytogenetic and molecular analyses were performed to characterize fetal features with tetrasomy 21. Results Prenatal ultrasound examination revealed an isolated complete atrioventricular septal defect with normal karyotype on amniotic fluid. After termination of pregnancy, clinical examination of the fetus evoked trisomy 21 or Down syndrome. Chromosomal microarray analysis and FISH on lung tissue showed a mosaicism with four copies of chromosome 21 (tetrasomy 21). Conclusion Our observation and the review of the literature reported the possibility of very weak mosaicism and disease‐causing confined tissue‐specific mosaicism in fetus or alive patients with chromosome 21 aneuploidy, mainly Down syndrome. In case of clinical diagnosis suggestive of Down syndrome, attention must be paid to the risk of false‐negative test due to chromosomal mosaicism (very weak percentage, different tissue distribution). To overcome this risk, it is necessary to privilege the diagnostic techniques without culture step and to increase the number of cells and tissues analyzed, if possible. This study highlights the limits of microarray as the unique diagnostic approach in case of weak mosaic and French cytogenetics guidelines recommend to check anomalies seen in microarray by another technique on the same tissue.

Background: Massively parallel sequencing of maternal cell-free DNA (cfDNA) is widely used to test fetal genetic abnormalities in non-invasive prenatal testing (NIPT). However, sequencing-based approaches are still of high cost. Building upon previous knowledge that placenta, the main source of fetal circulating DNA, is hypomethylated in comparison to maternal tissue counterparts of cfDNA, we propose that targeting either unmodified or 5-hydroxymethylated CG sites specifically enriches fetal genetic material and reduces numbers of required analytical sequencing reads thereby decreasing cost of a test. Methods: We employed uTOPseq and hmTOP-seq approaches which combine covalent derivatization of unmodified or hydroxymethylated CG sites, respectively, with next generation sequencing, or quantitative real-time PCR. Results: We detected increased 5-hydroxymethylcytosine (5hmC) levels in fetal chorionic villi (CV) tissue samples as compared with peripheral blood. Using our previously developed uTOP-seq and hmTOP-seq approaches we obtained whole-genome uCG and 5hmCG maps of 10 CV tissue and 38 cfDNA samples in total. Our results indicated that, in contrast to conventional whole genome sequencing, such epigenomic analysis highly specifically enriches fetal DNA fragments from maternal cfDNA. While both our approaches yielded 100% accuracy in detecting Down syndrome in fetuses, hmTOP-seq maintained such accuracy at ultra-low sequencing depths using only one million reads. We identified 2164 and 1589 placenta-specific differentially modified and 5-hydroxymethylated regions, respectively, in chromosome 21, as well as 3490 and 2002 Down syndrome-specific differentially modified and 5-hydroxymethylated regions, respectively, that can be used as biomarkers for identification of Down syndrome or other epigenetic diseases of a fetus. Conclusions: uTOP-seq and hmTOP-seq approaches provide a cost-efficient and sensitive epigenetic analysis of fetal abnormalities in maternal cfDNA. The results demonstrated that T21 fetuses contain a perturbed epigenome and also indicated that fetal cfDNA might originate from fetal tissues other than placental chorionic villi. Robust covalent derivatization followed by targeted analysis of fetal DNA by sequencing or qPCR presents an attractive strategy that could help achieve superior sensitivity and specificity in prenatal diagnostics. [ABSTRACT FROM AUTHOR]

Introduction: Contingent cell-free (cf) DNA screening on the basis of the first-trimester combined test (FCT) results has emerged as a cost-effective strategy for screening of trisomy 21 (T21).Objectives: To assess performance, patients' uptake, and cost of contingent cfDNA screening and to compare them with those of the established FCT.Methods: This is a prospective cohort study including all singleton pregnancies attending to their FCT for screening of T21 at 2 university hospitals in South Spain. When the FCT risk was ≥1:50, there were major fetal malformations, or the nuchal translucency was ≥3.5 mm, women were recommended invasive testing (IT); if the risk was between 1:50 and 1:270, women were recommended cfDNA testing; and for risks bellow 1:270, no further testing was recommended. Detection rate (DR), false-positive rate (FPR), patients' uptake, and associated costs were evaluated.Results: We analyzed 10,541 women, including 46 T21 cases. DR of our contingent strategy was 89.1% (41/46) at 1.4% (146/10,541) FPR. Uptake of cfDNA testing was 91.2% (340/373), and overall IT rate was 2.0%. The total cost of our strategy was €1,462,895.7, similar to €1,446,525.7 had cfDNA testing not been available.Conclusions: Contingent cfDNA screening shows high DR, low IT rate, and high uptake at a similar cost than traditional screening. [ABSTRACT FROM AUTHOR]

Objective: To determine the outcome of chorionic villus sampling for prenatal diagnosis of inherited diseases. Methodology: This descriptive study was conducted on 70 antenatal ladies having 11 to 14 weeks singleton pregnancy and with history of genetic disorders in family or children. It was carried in the Department of Obstetrics and Gynaecology, Lady Reading Hospital, Peshawar. Chorionic villus sampling (CVS) was performed by Obstetrics and Gynae consultants via transabdominal route under local anaesthesia and ultrasound guidance. Written informed consent was taken from all the participating couples before starting the process. By using SPSS version 23, statistical analysis was done. Results: A total of 70 samplings were done. Miscarriage as a result of the procedure occurred in 1/70 (1.42%), significant pain requiring intramuscular analgesia occurred in 40 (57%) patients and there were no reported cases of infection. Failure to retrieve sample occurred in 4 (5.7%) patients requiring repeat procedure after 10 days. 3 (4.2%) patients reported vaginal bleeding within a week after the procedure. After DNA analysis of the submitted samples, it showed thalassemia major 15 (21.42%), thalassemia minor 30 (42.85%), no mutation 22 (31.42%) and down syndrome 1 (1.42%). Conclusion: Chorionic villus sampling was found to be a safe procedure for prenatal diagnosis of genetic disorders in first trimester. [ABSTRACT FROM AUTHOR]

First‐trimester combined screening (FTS) has been offered to all pregnant women in Iceland since 2003. Individuals with high‐risk FTS results are offered an invasive test option with a ≤1% risk of fetal loss. This study gives insight into the prenatal screening and diagnosis experiences and preferences of 101 women who underwent FTS in Iceland in the years 2012–2016, comparing the experience of those who received false‐positive FTS results to those who received true‐negative results. Retrospective patient‐reported anxiety levels at the time of receiving FTS results were significantly higher in those who received false‐positive results compared to those who received true‐negative results. For a subset of these participants, the anxiety lasted through pregnancy, and for a smaller subset, it lasted even longer. Non‐invasive prenatal testing (NIPT) is currently not offered in Iceland, aside from the rare exceptional case. Given the extremely low false‐positive rates of NIPT, we believe NIPT is worth considering as Iceland's standard first‐tier screening method for trisomy 13, 18, and 21. We believe the findings of this study are beneficial not only for Iceland but also for other countries where FTS is the first‐tier prenatal screening method or the only offered test. Additionally, only 21% of participants in our study reported that they had heard of NIPT, which emphasizes the need for comprehensive NIPT pretest information to be available prior to its uptake to ensure informed and autonomous decision‐making. [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to determine whether Levey-Jennings charts, which are widely used in clinical laboratories, can be used to create standardized internal quality controls (IQCs) for prenatal molecular diagnosis. Methods: Aneuploid amniocyte lines with trisomy 13, 21, and 18, and 47,XXY were established by transfection with SV40LTag-pcDNA3.1(−)and combined at different ratios to generate aneuploidy chimeric quality-control cell mixtures A to H. These quality-control cells were then used to calculate the X ¯ , X ¯ ±1 standard deviation (SD), X ¯ ±2 SD, and X ¯ ±3 SD values to develop standardized IQCs for methods used for the prenatal diagnosis of aneuploidies such as FISH. Results: Methods for constructing aneuploid amniocyte lines were developed and a set of quality-control cells (A-H) were prepared. The X ¯ ±1 SD, X ¯ ±2 SD, and X ¯ ±3 SD values of these quality-control cells for trisomy 13 and 21 were 10.2 ± 1.7, 10.2 ± 3.4, and 10.2 ± 5.1, and 90.3 ± 2.3, 90.3 ± 4.6, and 90.3 ± 6.9, respectively. Based on the values and Levey-Jennings charts, a set of standardized IQCs for prenatal diagnosis such as FISH were established. Conclusions: This method resolves the problems of a shortage of quality-control materials and a lack of quality-control charts in prenatal molecular diagnosis such as NIPT, NGS, aCGH/SNP, PCR, and FISH. Levey-Jennings chart-based IQCs for prenatal diagnosis such as FISH can be used to easily monitor whether IQC results are within acceptable limits, and then infer whether the diagnostic results for clinical samples are reliable. We expect that this standardized IQC will be useful for a wide range of molecular diagnostic laboratories. [ABSTRACT FROM AUTHOR]

Background: Non-invasive prenatal testing (NIPT) has been established as a routine prenatal screening to assess the risk of common foetal aneuploidy disorder (trisomy 21, 18, and 13). NIPT has high sensitivity and high specificity, but false positive and false negative results still exist. False negative NIPT results involving Down syndrome are rare, but have a high clinical impact on families and society. Case presentation: We described a case of a foetus that tested "negative" for trisomy 21 (Z-score was 0.664) by NIPT based on the semiconductor sequencing platform (SSP). The foetal fraction of cell-free DNA was 16.9%; this percentage was much larger than the threshold of 4% for obtaining accurate NIPT results. However, postnatally, the newborn was diagnosed with Down syndrome with the 46,XY,der(21;21)(q10;q10),+ 21 karyotype. Conclusions: We presented a case of false negative NIPT results, which may occur through biological mechanisms rather than poor quality, technical errors or negligence. It is imperative for clinical geneticists and their patients to understand that NIPT is still a screening test. [ABSTRACT FROM AUTHOR]