Mosaic trisomy 16 at amniocentesis in a pregnancy associated with positive non-invasive prenatal testing for trisomy 16, placental trisomy 16, intrauterine growth restriction,intrauterine fetal death,cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes,and prenatal progressive decrease of the aneuploid cell line

ObjectiveWe present mosaic trisomy 16 at amniocentesis in a pregnancy associated with positive non-invasive prenatal testing (NIPT) for trisomy 16, placental trisomy 16, intrauterine growth restriction (IUGR), intrauterine fetal death (IUFD), cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes and uncultured amniocytes, and prenatal progressive decrease of the aneuploid cell line.Case reportA 26-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of positive NIPT for trisomy 16 at 12 weeks of gestation. Amniocentesis revealed a karyotype of 47,XX,+16 [10]/46,XX[17], and simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (16) × 3 [0.43] consistent with 43% mosaicism for trisomy 16. She was referred for genetic counseling at 19 weeks of gestation, and a fetus with IUGR was noted to have a size equivalent to 16 weeks of gestation. At 23 weeks of gestation, the fetus manifested oligohydramnios, fetal cardiomegaly and severe IUGR (fetal size equivalent to 20 weeks of gestation). Repeat amniocentesis revealed a karyotype of 46,XX (20/20 colonies) in cultured amniocytes and mosaic trisomy 16 by aCGH in uncultured amniocytes. aCGH analysis on uncultured amniocytes revealed the result of arr 16p13.3q24.3 × 2.3, consistent with 30% (log₂ ratio = 0.2) mosaicism for trisomy 16. Quantitative fluorescence polymerase chain reaction (QF-PCR) assays on the DNA extracted from parental bloods and uncultured amniocytes excluded uniparental disomy (UPD) 16. The parental karyotypes were normal. IUFD was noted at amniocentesis. The pregnancy was subsequently terminated, and a 288-g female fetus was delivered with no phenotypic abnormalities. The umbilical cord had a karyotype of 46,XX (40/40 cells), and the placenta had a karyotype of 47,XX,+16 (40/40 cells). QF-PCR assays of the placenta confirmed a maternal origin of trisomy 16.ConclusionMosaic trisomy 16 at amniocentesis can be associated with positive NIPT for trisomy 16, placental trisomy 16, IUGR, IUFD, cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, and prenatal progressive decrease of the aneuploid cell line.     

无创产前基因检测在胎儿性染色体疾病筛查中的应用

目的探讨无创产前基因检测(non-invasive prenatal genetic testing,NIPT)在胎儿性染色体疾病中的临床价值。方法统计深圳市第二人民医院2016年3月至2019年6月行NIPT的16119例单胎孕妇中提示21-三体、18-三体、13-三体、性染色体异常和其他染色体异常的阳性率;对比2016年3月至2019年6月NIPT示“胎儿性染色体异常”与本院染色体核型结果。结果①NIPT对21-三体,18-三体,13-三体,性染色体异常和其他染色体异常筛查的阳性率分别为0.42%(68/16119),0.10%(16/16119),0.07%(11/16119),0.38%(61/16119)和0.22%(36/16119)。②47例“NIPT示胎儿性染色体异常”者中,确诊为性染色体疾病者26例,阳性预测值55.32%。其中,NIPT对胎儿性染色体数目偏多的阳性预测值为91.30%(21/23),对胎儿性染色体数目偏少的阳性预测值20.0%(4/20),对胎儿性染色体数目异常的阳性预测值25.0%(1/4)。结论NIPT可作为胎儿性染色体疾病的筛查方法,但由于其对性染色体偏少和性染色体数目异常的假阳性率较高,检测阳性者仍需要做侵入性产前诊断确诊。     

Low-level mosaic trisomy 9 at amniocentesis associated with a positive non-invasive prenatal testing for trisomy 9, maternal uniparental disomy 9, intrauterine growth restriction and a favorable fetal outcome in a pregnancy

ObjectiveWe present low-level mosaic trisomy 9 at amniocentesis associated with a positive non-invasive prenatal testing (NIPT) for trisomy 9, maternal uniparental disomy (UPD) 9, intrauterine growth restriction (IUGR) and a favorable fetal outcome in a pregnancy.Case reportA 41-year-old, gravida 3, para 0, woman underwent amniocentesis at 18 weeks of gestation because of NIPT at 10 weeks of gestation suspicious of trisomy 9 in the fetus. This pregnancy was conceived by in vitro fertilization (IVF). Amniocentesis revealed a karyotype of 47,XY,+9 [2]/46,XY[23]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (1–22) × 2, (X,Y) × 1 and detected no genomic imbalance. Polymorphic DNA marker analysis showed maternal uniparental heterodisomy 9 in the amniocytes. Prenatal ultrasound was normal. The woman was referred for genetic counseling at 22 weeks of gestation. The soluble fms-like tyrosine kinase (sFlt)/placental growth factor (PlGF) = 13.1 (normal < 38). There was no gestational hypertension. Continuing the pregnancy was advised. No repeat amniocentesis was performed because of persistent irregular contractions. IUGR was noted. A 2156-g phenotypically normal baby was delivered at 37 weeks of gestation. The cord blood and umbilical cord had a karyotype of 46,XY (40/40 cells). The placenta had a karyotype of 47,XY,+9 (40/40 cells). The parental karyotypes were normal. Quantitative fluorescence polymerase chain reaction (QF-PCR) on the DNA extracted from parental bloods, cord blood, umbilical cord and placenta revealed maternal uniparental heterodisomy 9 in cord blood and umbilical cord, and trisomy 9 of maternal origin in placenta. When follow-up at age three months, the neonate was normal in development and phenotype. The buccal mucosal cells had 3% (3/101 cells) mosaicism for trisomy 9 by interphase fluorescent in situ hybridization (FISH) analysis.ConclusionMosaic trisomy 9 at prenatal diagnosis should alert the possibility of UPD 9 and include a UPD 9 testing. Low-level mosaic trisomy 9 at amniocentesis can be associated with UPD 9 and a favorable fetal outcome.     

Clinical utility and cost of non-invasive prenatal testing with cfDNA analysis in high-risk women based on a US population

Abstract

Objective: Evaluate the clinical and economic consequences of fetal trisomy 21 (T21) screening with non-invasive prenatal testing (NIPT) in high-risk pregnant women.

Methods: Using a decision-analytic model, we estimated the number of T21 cases detected, the number of invasive procedures performed, corresponding euploid fetal losses and total costs for three screening strategies: first trimester combined screening (FTS), integrated screening (INT) or NIPT, whereby NIPT was performed in high-risk patients (women 35 years or older or women with a positive conventional screening test). Modeling was based on a 4 million pregnant women cohort in the US.

Results: NIPT, at a base case price of $795, was more clinically effective and less costly (dominant) over both FTS and INT. NIPT detected 4823 T21 cases based on 5330 invasive procedures. FTS detected 3364 T21 cases based on 108?364 procedures and INT detected 3760 cases based on 108?760 procedures. NIPT detected 28% and 43% more T21 cases compared to INT and FTS, respectively, while reducing invasive procedures by >95% and reducing euploid fetal losses by >99%. Total costs were $3786M with FTS, $3919M with INT and $3403M with NIPT.

Conclusions: NIPT leads to improved T21 detection and reduction in euploid fetal loss at lower total healthcare expenditures.     

Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China

PurposeTo evaluate the noninvasive prenatal testing (NIPT) results of 36,913 cases in Jiangxi province of central China and explore its application value in prenatal screening and diagnosis.MethodsThis retrospective analysis included 36,913 singleton pregnant women who underwent NIPT because of moderate-/high-risk pregnancy or voluntary requirements between January 2017 and December 2019 in our hospital. Chromosomal abnormalities such as trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs) were judged by standard Z-score analysis. Positive NIPT results were confirmed by amniocentesis and karyotyping. Pregnancy outcomes were followed up via telephone interview.ResultsA total of 1.01% (371/36,913) positive cases were detected by NIPT, comprising 137, 46, 31, and 157 cases of T21, T18, T13, and SCAs, respectively. A total of 116 of T21, 27 of T18, 13 of T13, and 51 of SCAs were confirmed to be true positive; all normal cases that had been followed up were verified to be true negative. The NIPT sensitivity in T21, T18, T13, and SCAs was 100.00% individually, whereas the specificity was 99.94% (36,488/36,509), 99.95% (36,579/36,598), 99.95% (36,594/36,612), and 99.72% (36,472/36,574), respectively. Furthermore, the negative predictive values of T21, T18, T13, and SCAs were all 100%, while the positive predictive values were 84.67%, 58.70%, 41.94%, and 33.33%, respectively.ConclusionNIPT is highly sensitive and has a low false positive rate in testing clinically significant fetal aneuploidies of general reproductive women. However, this technique cannot substitute for amniocentesis and karyotyping, and detailed genetic counseling is also essential for the high-risk group of NIPT.     

Noninvasive prenatal detection of fetal sex chromosome abnormalities using the semiconductor sequencing platform (SSP) in Southern China

BackgroundNoninvasive prenatal testing (NIPT) has been widely used to screen for fetal aneuploidies, including fetal sex chromosome aneuploidies (SCAs). However, there is less information on the performance of NIPT in detecting SCAs.MethodsA cohort of 47,800 pregnancies was recruited to review the high-risk NIPT results for SCAs. Cell-free fetal DNA (cffDNA) was extracted and sequenced. All NIPT high-risk cases were recommended to undergo invasive prenatal diagnosis for karyotyping analysis and chromosome microarray analysis (CMA).ResultsA total of 238 high-risk cases were detected by NIPT, including 137 cases of 45,X, 27 cases of 47,XXX, and 74 cases of 47,XYY/47,XXY. Prenatal diagnosis, including karyotyping analysis and CMA, was available in 170 cases. The positive predictive value (PPV) was 30.00% for 45,X, 70.58% for 47,XXX, and 81.13% for 47,XYY/47,XXY. In addition, 13 cases of sex chromosome mosaicism and 9 cases of sex chromosome CNVs were incidentally found in this study.ConclusionOur study showed that NIPT was reliable for screening SCAs based on a large sample, and it performed better in predicting sex chromosome trisomies than monosomy X. Our study will provide an important reference for clinical genetic counseling and further processing of the results.     

Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis

Objective: To estimate the cost-effectiveness of fetal aneuploidy screening in the general pregnancy population using non-invasive prenatal testing (NIPT) as compared to first trimester combined screening (FTS) with serum markers and NT ultrasound.

Methods: Using a decision-analytic model, we estimated the number of fetal T21, T18, and T13 cases identified prenatally, the number of invasive procedures performed, corresponding normal fetus losses, and costs of screening using FTS or NIPT with cell-free DNA (cfDNA). Modeling was based on a 4 million pregnant women cohort, which represents annual births in the U.S.

Results: For the general pregnancy population, NIPT identified 15% more trisomy cases, reduced invasive procedures by 88%, and reduced iatrogenic fetal loss by 94% as compared to FTS. The cost per trisomy case identified with FTS was $497?909. At a NIPT unit, cost of $453 and below, there were cost savings as compared to FTS. Accounting for additional trisomy cases identified by NIPT, a NIPT unit cost of $665 provided the same per trisomy cost as that of FTS.

Conclusions: NIPT in the general pregnancy population leads to more prenatal identification of fetal trisomy cases as compared to FTS and is more economical at a NIPT unit cost of $453.     

Non-invasive prenatal testing: impact on invasive prenatal diagnosis at a mainland Chinese tertiary medical center

Objective: We describe the changes over a 4-year period in the number of diagnostic testing after the introduction of non-invasive prenatal testing (NIPT).

Methods: The rate of NIPT as an indication in women who received amniocentesis, and the number of amniocentesis required for detection of one case with major aneuploidy were compared between a 1-year baseline period before the introduction of NIPT, and the 3 years following NIPT introduction.

Results: A total of 7536 amniocentesis procedures were performed over the 4-year study period. During the baseline period of the year 2011, the number of invasive testing required for detection of one common trisomy was 57. During the first 2 years that NIPT was offered, NIPT averaged 1.7 percent of the total indications for amniocentesis, and the required number of invasive testing decreased to 30. With the increase of the percentage of NIPT during the 3rd year, the required number of invasive testing further decreased to 26.

Conclusion: After the clinical introduction of NIPT, invasive prenatal diagnostic testing had not decreased at a Chinese prenatal diagnostic unit, but a remarkably improved detection rate of major aneuploidies in diagnostic procedures was observed.     

无创基因检测筛查胎儿染色体异常的效果及其与孕妇年龄和检测孕周相关性的探讨

目的 分析我院无创基因检测对胎儿常见染色体非整倍体异常的检测效果,探讨不同检测孕周、孕妇年龄与检测效果指标的相关性.方法 选择自2013年6月至2019年4月在北京大学深圳医院行无创产前基因检测(non-invasive prenatal DNA testing,NIPT)的孕妇,对检测结果高风险者进行羊水染色体核型分...     

The role of ultrasound in women with a positive NIPT result for trisomy 18 and 13

ObjectiveThe aim of this study was to evaluate the usefulness of ultrasound in pregnancies with a positive non-invasive prenatal testing (NIPT) result for trisomy 18/13.Materials and methodsDuring a four-year period, the pregnant women who were referred for invasive genetic testing because of positive NIPT results for trisomy 18/13 were included in this study. An in-depth ultrasound was done for these patients before invasive procedures. The data of fetal ultrasound and cytogenetic results were collected.ResultsThere were 81 patients with a positive NIPT result for trisomy 18/13, including 39 (30 positive for trisomy 18; 9 positive for trisomy 13) within 12–14 weeks of gestation, and 42 (31 positive for trisomy 18; 11 positive for trisomy 13) within 15–22 weeks. The PPV of NIPT was 60.7% for trisomy 18, and 30% for trisomy 13, respectively. When adding ultrasound to NIPT, the new PPV for trisomy 18 was 100%, and the negative predictive value (NPV) was 92.3%, with a NPV of 85.7% in the first trimester and a NPV of 100% in the second trimester, respectively. The new PPV and NPV for trisomy 13 were 100% and 100%, respectively.ConclusionBy adding ultrasound to the NIPT, we achieved much higher PPVs and NPVs for trisomy 18/13. A normal scan can help to alleviate stress in parents caused by false positive NIPT results.     

Noninvasive prenatal testing (NIPT) detects variant of Turner syndrome not detectable by fluorescent in situ hybridization

Abstract

Introduction: Noninvasive prenatal testing (NIPT) is a reliable screening method for fetal aneuploidy detection of trisomy 18, 13, 21 along with few sex chromosome abnormalities monosomy X, XXX, XXY (Klinefelter), XYY (Jacob) syndromes and certain microdeletions which include cri-du-chat, DiGeorge, 1p36, Angelman, and Prader-Willi syndromes in comparison to the available screening methods. Prenatal screening of Turners syndrome is possible by ultrasound in certain conditions only. Recently benefits of early detection and treatment of Turners syndrome has been emphasized, enforcing on accurate and early screening prenatally.

Case details: The current case emphasizes on the reliability of NIPT testing which comes with an advantage of early screening. A 24-year-old primi gravida was referred for NIPT as she tested for high risk on biochemical screening. The Panorama? NIPT results showed low risk for trisomies, 21, 18, and 13 but high risk of monosomy X and was advised confirmatory amniocentesis. The fluorescence in situ hybridization (FISH) report revealed no numerical abnormality detected for any of the five chromosomes tested. On receiving this discordant report, the sample was rerun for NIPT, to rule out any laboratory-related issues. The result obtained on a rerun was consistent with the first report and showed monosomy X again. The karyotype report was available three weeks later and a rare variant of Turners syndrome was identified.

Discussion: Panorama? NIPT considers single nucleotide polymorphisms spread across the chromosomes for analysis, different variants of aneuploidy can be picked up in comparison to FISH, similar to the current case wherein it could not as it was a centromeric probe. Reported first case of X chromosome variant detected by NIPT confirmed by karyotyping, missed by FISH.     

无创DNA检测在诊断高龄孕妇胎儿非整倍体中的应用

目的:探讨高龄妊娠胎儿染色体异常的风险以及无创DNA产前检测(NIPT)在诊断高龄孕妇胎儿非整倍体染色体病中的应用价值。方法:选择≥35岁的高龄孕妇2714例,按年龄分为35~39岁,≥40岁两组,采用NIPT高通量测序检测孕妇血浆游离DNA,并对检测结果提示21-三体、18-三体、13-三体及性染色体高风险者行羊膜腔穿刺术及胎儿染色体核型分析,对检测结果阴性者通过电话随访进行验证。计算NIPT检测的敏感度、特异度、阳性预测值、阴性预测值及Youden指数。结果:2714例高龄孕妇NIPT检测结果提示胎儿非整倍体染色体异常高风险47例,6例高风险孕妇拒绝侵入性产前诊断,余41例高风险孕妇行羊膜腔穿刺术及羊水细胞染色体核型分析,结果显示21-三体19例,18-三体1例,13-三体2例,性染色体异常7例。与现有的金标准羊膜腔穿刺术核型分析相比较,NIPT对高龄孕妇除外性染色体异常的胎儿非整倍体染色体异常检出敏感度为100.00%,特异度为99.93%,阳性预测值为90.91%,阴性预测值为100.00%,Youden指数为0.99。进一步通过年龄分组发现,40岁及以上年龄组异常率显著高于35~39岁年龄组(P=0.011)。结论:高龄孕妇可通过NIPT快速、安全地筛查出胎儿非整倍体染色体异常,减少侵入性产前检测比例,降低胎儿出生缺陷率。     

A two-year experience of non-invasive prenatal testing (NIPT) at an urban tertiary medical center in South Korea

ObjectiveTo report our experience of implementing non-invasive prenatal testing (NIPT) in a tertiary urban academic medical center in South Korea.Materials and methodsAn observational retrospective study of singleton and twin pregnancies that underwent prenatal screening for fetal aneuploidy from July 2016 to April 2018 was conducted. Demographics of the study population electing NIPT versus those opting the integrated test were compared. We also assessed clinical significant factors influencing cfDNA fetal fraction in NIPT.ResultsAmong the 817 women who underwent serum screening tests during the study period, 490 women (60.0%) chose the integrated test while 327 women (40.0%) chose NIPT. Compared to the integrated test group, women in the NIPT group were older (mean age 34.7 ± 3.7 vs. 32.6 ± 3.4; p-value < 0.01), multiparous (47.1% vs. 39.8%; p-value = 0.046), and had higher rate of previous abortion history (28.4% vs. 21.6%; p-value = 0.033). A significant decrease in the number of invasive diagnostic tests was observed since the adoption of NIPT. The screen negative and positive rates of the integrated test group for fetal aneuploidy were 95.3% and 4.7%, respectively while those of the NIPT group were 95.9% and 1.2%, respectively. The rate of inadequate cfDNA fetal fraction was 3.0%. Low fetal fraction was associated with higher maternal age, body weight and BMI.ConclusionsThe implementation of NIPT has significantly affected the practice pattern of prenatal aneuploidy screening by replacing the integrated test and decreasing invasive diagnostic tests.     

Prenatal diagnosis and molecular cytogenetic characterization of a de novo deletion of 4q34.1→qter associated with low PAPP-A and low PlGF in the first-trimester maternal serum screening,congenital heart defect on fetal ultrasound and a false negative non-invasive prenatal testing (NIPT) result

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of a de novo deletion of 4q34.1→qter associated with low pregnancy associated plasma protein-A (PAPP-A) and low placental growth factor (PlGF) in the first-trimester maternal serum screening, congenital heart defect (CHD) on fetal ultrasound and a false negative non-invasive prenatal testing (NIPT) result.Case ReportA 40-year-old, primigravid woman underwent amniocentesis at 20 weeks of gestation because of advanced maternal age. This pregnancy was conceived by in vitro fertilization (IVF) and embryo transfer (ET). First-trimester maternal serum screening at 12 weeks of gestation revealed low PAPP-A [0.349 multiples of the median (MoM)] and low PlGF (0.299 MoM) and showed a risk for fetal trisomy 21 and trisomy 13. However, NIPT detected no genomic imbalance and a normal result. Nevertheless, level II ultrasound revealed ventricular septal defect, single umbilical artery and a small brain midline cyst. Amniocentesis revealed a karyotype of 46,XX,del(4)(q34.1) and a 17.8-Mb deletion of 4q34.1q.35.2 on array comparative genomic hybridization (aCGH) analysis. The parental karyotypes were normal. The pregnancy was terminated at 23 weeks of gestation, and a malformed fetus was delivered with craniofacial dysmorphism. Postnatal cytogenetic analysis of the placenta confirmed the prenatal diagnosis. There was a 17.8-Mb deletion of 4q34.1q.35.2 encompassing the genes of HAND2, SORBS2 and DUX4. Polymorphic DNA marker analysis on the parental bloods and cord blood showed a paternal origin of the deletion.ConclusionAn abnormal first-trimester maternal serum screening result along with abnormal fetal ultrasound should alert the possibility of fetal aneuploidy, and amniocentesis is indicated even in the presence of a normal NIPT result.     

Low-level mosaic trisomy 13 at amniocentesis in a pregnancy associated with a positive NIPT result suspicious of trisomy 13, a CVS result of mosaic trisomy 13, cytogenetic discrepancy in various tissues and a favorable fetal outcome

ObjectiveWe present low-level mosaic trisomy 13 at amniocentesis in a pregnancy associated with a positive non-invasive prenatal testing (NIPT) result suspicious of trisomy 13, a chorionic villus sampling (CVS) result of mosaic trisomy 13, cytogenetic discrepancy in various tissues and a favorable fetal outcome.Case reportA 29-year-old, gravida 2, para 1, woman underwent amniocentesis at 20 weeks of gestation because of a positive NIPT result (Z-score = 20.9, positive ≥3) suspicious of trisomy 13 at 11 weeks of gestation and a CVS result of mosaic trisomy 13 at 14 weeks of gestation. At 14 weeks of gestation, CVS revealed the multiplex ligation-dependent probe amplification (MLPA) result of rea X,Y (P095) × 1, 13 (P095) × 3, 18,21 (P095) × 2/X,Y (P095) × 1, 13,18,21 (P095) × 2 and a karyotype of 48,XY,+13,+mar [9]/47,XY,+mar[16]. She was referred to the hospital for genetic counseling at 15 weeks of gestation, and cytogenetic analysis of parental blood revealed 47,XY,+mar in the father and 46, XX in the mother. Fluorescence in situ hybridization (FISH) analysis on the paternal blood showed that the extra dicentric marker was derived from chromosome 15 without the locus SNRPN (15q11.2), and the result was 47,XY,+mar.ish dic(15) (D15Z1++, SNRPN-, PML-)[20]. Amniocentesis at 20 weeks of gestation revealed a karyotype of 47,XY,+mar pat (20/20). Simultaneous interphase FISH analysis on uncultured amniocytes revealed 32% (32/100 cells) mosaicism for trisomy 13. Quantitative fluorescence polymerase chain reaction (QF-PCR) analysis using the DNA extracted from the parental bloods and uncultured amniocytes excluded uniparental disomy (UPD) 13. Prenatal ultrasound findings were normal. The woman was advised to continue the pregnancy, and a phenotypically normal 2708-g male baby was delivered at 38 weeks of gestation, The cord blood, umbilical cord and placenta had the karyotypes of 47,XY,+mar pat and did not have UPD 13. When follow-up at age two months, the neonate was phenotypically normal. FISH analysis on buccal mucosal cells detected 5.3% (5/95 cells) mosaicism for trisomy 13, compared with 0% in the normal control.ConclusionLow-level mosaic trisomy 13 at amniocentesis can be associated with a positive NIPT result suspicious of trisomy 13, a CVS result of mosaic trisomy 13, cytogenetic discrepancy in various tissues and a favorable fetal outcome.     

Detection of fetal trisomy 9 mosaicism by noninvasive prenatal testing through maternal plasma DNA sequencing

Objective

Noninvasive prenatal testing (NIPT) is widely used as a powerful screening tool to detect common aneuploidies. However, its application for detection of rare chromosomal abnormalities remains inconclusive.

Association of non-invasive prenatal testing and chromosomal microarray analysis for prenatal diagnostics

Abstract

The purposes of this study is to examine possibility to use combination of non-invasive prenatal testing (NIPT) and chromosomal microarray analysis (CMA) for prenatal diagnostics and their advantages between combined first-trimester screen with confirmation by karyotyping of CVS or amniocytes. A total of 1968 pregnant women, in this study, have undergone prenatal screening and/or diagnostic tests. NIPT is more suitable and efficient for the detection of aneuploidy. However, this test has limitations for detection deletions/duplications. Use of CMA for confirmation of some NIPT findings or as first test for women with ultrasound abnormalities can detect small imbalances in chromosomes. Combination of NIPT and CMA allows a higher prenatal detection of chromosomal abnormalities.     

Prenatal diagnosis of pseudomosaicism for trisomy 20 at amniocentesis with a negative non-invasive prenatal testing (NIPT) result in a pregnancy with a favorable outcome

ObjectiveWe present prenatal diagnosis of pseudomosaicism for trisomy 20 at amniocentesis with a negative non-invasive prenatal testing (NIPT) result in a pregnancy with a favorable outcome.Case reportA 33-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation, which revealed a karyotype of 47,XX,+20[8]/46,XX[31]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (1–22,X) × 2, consistent with no genomic imbalance. She was referred to the hospital for repeat amniocentesis at 23 weeks of gestation. At repeat amniocentesis, cultured amniocytes had a karyotype of 47,XX,+20[2]/46,XX[33]. The parental karyotypes were normal. Simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes using SurePrint G3 Unrestricted CGH ISCA v2, 8 × 60 K (Agilent Technologies, Santa Clara, CA, USA) revealed no genomic imbalance, or arr (1–22,X) × 2, Y × 0. Interphase fluorescence in situ hybridization (FISH) analysis using the bacterial artificial chromosome (BAC) probes of RP11-266K16 [20q13.33; fluorescein isothiocyanate (FITC), spectrum green] and RP11-348I14 (20q11.1-q11.21; Texas Red, spectrum red) detected trisomy 20 signals in 4/104 uncultured amniocytes (3.8%), compared with 0/100 in the normal control. Polymorphic DNA marker analysis using the DNA extracted from uncultured amniocytes and parental bloods excluded uniparental disomy 20. NIPT analysis on maternal blood revealed a negative result without gene dosage increase in chromosome 20. The pregnancy was carried to term, and a healthy 2830-g female baby was delivered with no phenotypic abnormality. Both cord blood and placenta had a karyotype of 46,XX.ConclusionNIPT is useful for rapid differential diagnosis of pseudomosaicism from true mosaicism in case of mosaic trisomy 20 at amniocentesis.     

不同产前筛查方案对胎儿染色体异常检出效率的比较

目的 探讨不同产前筛查方案对胎儿染色体异常的检出效率.方法 应用时间分辨免疫荧光法对24986例孕妇进行母体血清学二联筛查,根据风险值及后续的检查方案不同将人群分为高风险直接进行羊水穿刺组(A1组)、高风险行无创产前检测(non-invasive prenatal testing,NIPT)组(A2组)、临界风险进行超...     

Non-invasive prenatal testing (NIPT): Europe’s first multicenter post-market clinical follow-up study validating the quality in clinical routine

Purpose

Non-invasive prenatal tests (NIPT) for the determination of fetal aneuploidies from maternal blood are firmly established in clinical routine. For the first time, the accuracy of an NIPT for the determination of trisomies 21, 18 and 13 in singleton pregnancies was assessed by means of a prospective German-wide multicenter post-market clinical follow-up study, to reliably evaluate the quality in clinical routine.

Methods

The study covered the indications for testing, the test results, the rate of invasive diagnostics and the pregnancy outcome. 2232 cases were tested for trisomy 21. Of these, 1946 cases were additionally examined for trisomy 18 and 13.

Results

Sensitivity and specificity for trisomy 21 (43/43) and for trisomy 13 (2/2) were 100%, for trisomy 18 the sensitivity was 80% (4/5) with a specificity of 99.8%. Three false-positive results for trisomy 18 were observed (FPR 0.15%). The no-call rate was 0.5%. In this subgroup, 27.3% (3/11) aneuploidies were diagnosed. The rate of invasive procedures was 2.6%.

Conclusion

NIPT provides a very high quality for the fetal trisomies 21, 13 and 18 in clinical routine. The results support the recommendation that NIPT should be offered after genetic counseling and only in conjunction with a qualified ultrasound examination.