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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 163-168

Clinical performance of cell-free fetal DNA testing for fetal aneuploidies and subchromosomal deletions/duplications in a cohort of 19,531 pregnancies

Department of Laboratory Medicine, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China

Date of Submission15-Feb-2020
Date of Decision22-Apr-2020
Date of Acceptance28-Jun-2020
Date of Web Publication27-Aug-2020

Correspondence Address:
Chun-Mei Ying
Department of Laboratory Medicine, Obstetrics and Gynecology Hospital, Fudan University, No 419 Fangxie Road, Shanghai 200011
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Source of Support: None, Conflict of Interest: None

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Objective: We aim to assess the clinical performance of cell-free fetal DNA (cffDNA) testing for detecting common fetal aneuploidies as well as subchromosomal deletions/duplications and explore the pregnancy decisions in screen-positive cases.
Methods: A cohort of 19,531 pregnant women was offered cffDNA testing for detection of trisomies 21, 18, and 13 (T21, T18, and T13); sex chromosome aneuploidies (SCAs); and subchromosomal deletions/duplications. Screen-positive cases were confirmed by karyotyping and single-nucleotide polymorphism array analysis.
Results: A total of 47 cases failed the test. The overall screen-positive rate of chromosomal abnormalities was 1.07% (208/19,484), including 57 cases with T21, 18 cases with T18, 7 cases with T13, 106 cases with SCAs, and 20 cases of subchromosomal deletions/duplications. Positive predictive values were 91.30% (42/46), 38.46% (5/13), 33.33% (2/6), 41.33% (31/75), and 27.78% (5/18), respectively. There was no significant difference in the screening of fetal chromosomal aneuploidies in the high-risk group compared with the low-risk group (P > 0.05). All of the pregnant women who had confirmed fetal T21, T18, or T13 terminated their pregnancies, except for a case of T13 mosaic, whereas 45.16% (14/31) of women with fetal SCAs continued their pregnancies. Furthermore, 17 pregnant women with positive screens for T21, T18, or T13 without a subsequent diagnosis chose to terminate their pregnancy, whereas 29 of 31 women with SCAs chose to continue their pregnancies.
Conclusions: CffDNA testing exhibited good screening accuracy for T21, T18, and T13 and also contributed to detecting fetal SCAs and subchromosomal deletions/duplications. Pregnant women with fetal 47, XXX or 47, XYY were more willing to terminate their pregnancy than those with fetal 45, X or 47, XXY.

Keywords: Cell-free DNA Prenatal Testing; Sex Chromosome Aneuploidies; Subchromosomal Deletions/Duplications; Trisomies

How to cite this article:
Chen YS, Wu YQ, Zhang Y, Ying CM. Clinical performance of cell-free fetal DNA testing for fetal aneuploidies and subchromosomal deletions/duplications in a cohort of 19,531 pregnancies. Reprod Dev Med 2020;4:163-8

How to cite this URL:
Chen YS, Wu YQ, Zhang Y, Ying CM. Clinical performance of cell-free fetal DNA testing for fetal aneuploidies and subchromosomal deletions/duplications in a cohort of 19,531 pregnancies. Reprod Dev Med [serial online] 2020 [cited 2021 Jan 24];4:163-8. Available from: https://www.repdevmed.org/text.asp?2020/4/3/163/293695

  Introduction Top

Chromosomal abnormalities occur in every 1 of 160 live births. Of these, about 1 out of every 800–1,000 children is born with Down's syndrome (trisomy 21, T21), 1 out of 3,500–7,000 children is born with trisomy 18 (T18), and 1 out of 5,000–6,000 children is born with trisomy 13 (T13). Sex chromosome aneuploidies (SCAs), including 45, X, 47, XXX, 47, XXY, and 47, XYY, occur once in every 1 in 9,600, 1 in 1,000–2,000, 1 in 800, and 1 in 1,080 live births, respectively.[1] Prenatal screening is an important method of detecting birth defects. The traditional prenatal screening based on maternal age, serum biochemical results, nuchal translucency, and ultrasonic findings primarily detect T21, T18, and neural tube defects. For T21, the detection rate is about 60% to 95%, whereas the false-positive rate (FPR) is nearly 5%.[2],[3],[4] Those screening high-risk fetal chromosome aneuploidies rely on invasive testing, such as chorionic villus sampling or amniocentesis using karyotyping. Current invasive procedures still have a risk of miscarriage (approximately 0.5%–1.0%).[5]

In 1997, Lo et al. found cell-free fetal DNA (cffDNA) in circulating plasma of pregnant women.[6] Owing to the development of massively parallel sequencing, the discovery of cffDNA testing has facilitated the development of safer and earlier testing procedures based on a simple sampling of maternal blood. Currently, cffDNA testing has been widely used to screen for fetal aneuploidies, including fetal T21, T18, and T13. Numerous studies have shown that cffDNA testing has a higher detection rate and lower FPR compared with first-trimester screening for fetal chromosome aneuploidy.[7],[8],[9],[10]

According to the Chinese clinical guidelines published in 2016 [Supplementary Table 1], high-risk pregnant women, including those of advanced maternal age, with high-risk serum biochemical screening results, or with abnormal ultrasound markers, comprise the primary group for whom cffDNA testing is recommended. However, the American College of Medical Genetics and Genomics recommends cffDNA testing for the entire population.[11] Several studies have reported on the performance of cffDNA testing in low-risk populations.[12] Our survey enrolled pregnancies classified as either high- or low-risk through traditional screening methods.

In recent years, further expansion of cffDNA testing has focused on screening for fetal SCAs (45, X, 47, XXX, 47, XXY, and 47, XYY), but the accuracy for SCA was with conflicting and limited results. One possible explanation is maternal SCA (full or mosaic).[13],[14] Furthermore, chromosome X is of highly variable amplification because of its lower GC content.[15]

In the meantime, with the widespread of sequencing technology, subchromosomal deletions/duplications that could not be detected by karyotyping are now able to be detected. Subchromosomal deletions or duplications are usually associated with severe syndromes such as DiGeorge syndrome, Prader–Willi/Angelman syndromes, Cri du chat syndrome, and 1p36 deletion syndrome.[8],[16],[17] It is well known that 22q11.2 deletion syndromes, also called DiGeorge syndrome, may cause congenital heart disease.[18] Subchromosomal deletions/duplications can also be detected by cffDNA testing,[19],[20],[21] although they are not recommended for routine screening at present. Hence, a clinical validation survey is needed.

Our study evaluated the performance of cffDNA testing for detecting T21, T18, T13, and SCAs as well as subchromosomal deletions/duplications in a large population and compared the screening performance between low-risk and high-risk pregnancies. We also analyzed the outcomes of pregnancies that had positive results on cffDNA testing. Our study enrolled 19,531 pregnant women who were analyzed by cffDNA screening for common fetal aneuploidies and MMS.

  Methods Top

Ethical approval

Ethical approval was obtained from the Medicine Ethics Committee of Obstetrics and Gynecology Hospital of Fudan University (approval No. 2018-71). All pregnant women signed the informed consent upon enrollment and before cffDNA testing.

Pregnant women

This was a retrospective study of 19,531 pregnant women whose data were collected from the Obstetrics and Gynecology Hospital of Fudan University in China from May 2017 to May 2019. A total of 686 cases (3.51%) underwent cffDNA testing was failed once and tested twice. Among them, 152 cases (0.78%) were resampled after duplicate detection failure. Ultimately, 47 cases were considered failures by cffDNA testing mainly because of low fetal DNA fraction (<5%), providing a test failure rate of 0.24% (47/19,531). Eventually, the data were analyzed from the remaining 19,484 pregnancies. Detailed information and indications for cffDNA testing are summarized in [Supplementary Table 2]. The median maternal age was 31 years (range, 18–52 years). The group aged 30–34 years made up the majority (6,934, 35.46%) and the pregnant women over 35 years old were 24.27% of the group. The mean gestational age at the time of blood sampling was 16 weeks (range, 12–32 weeks), and 55.94% of the group had a gestational age from 12 to 16 weeks. The average maternal weight was 59.27 kg, and the average body mass index was 22.53 kg/m2. Indications for conducting cffDNA testing [Supplementary Table 2] included the following: approximately 24.27% (4,729/19,484) of the cases were aged 35 years or older, 7.26% (1,415/19,484) showed high-risk serum screening, 2.61% (509/19,484) had abnormal findings on ultrasound, and 10.80% (2105/19,484) had a diverse family history. Other cases (55.05%, 10,726/19,484) were considered low risk and did not have any of these indications for initial cffDNA testing.

We divided the pregnancies into a high-risk group and low-risk group based on known risk factors. Pregnancies in the high-risk group had at least one of the following risk factors: (1) advanced maternal age (≧35 years), (2) prior high-risk serum biochemical screening results (cutoff 1/380 for T21 or 1/334 for T18, depending on clinical criteria), (3) abnormal ultrasonographic markers, or (4) history of chromosomal abnormalities in pregnancy. Pregnancies in the low-risk group showed none of these risk factors.

Cell-free fetal DNA testing screening, karyotyping, and single-nucleotide polymorphism array procedure

CffDNA testing was performed in our laboratory according to the standard procedures as previously described.[12] Approximately 10 mL of maternal peripheral blood was collected into cell-free tubes. Plasma was prepared after a two-step centrifugation protocol of 1,600 ×g for 10 min, followed by 16,000 ×g for 10 min.[22] Plasma samples were stored at −20°C. CffDNA testing procedures, including cffDNA extraction (Berry Genomics Corporation), library construction, pooling, and sequencing, were subsequently performed using the Illumina Nextseq CN500 platform (Berry Genomics). Fetal chromosome aneuploidy risk was evaluated using a ratio Z-score. If the Z-score was & #124: Z & #124: >3, a high-risk result with subchromosomal deletions/duplications was indicated. If & #124: Z & #124: ≤3, a low-risk result was indicated.

Invasive prenatal diagnosis testing (karyotyping and single-nucleotide polymorphism [SNP] array) through amniocentesis was conducted for cffDNA screening-positive pregnancies. Amniotic fluid cells were cultured following karyotyping standards, including cell harvest, colchicine treatment, digestion, fixation, spread preparation, and banding. The accuracy of cffDNA testing was determined based on the results of fetal chromosomal karyotyping and SNP array. We analyzed 20 karyotypes and repeated three times for each sample. Sequencing reads were filtered and aligned to the human reference genome (hg19). Whole chromosome aneuploidies were confirmed by chromosomal karyotyping and subchromosomal deletions/duplications were confirmed by SNP array. Women who rejected the diagnosis were followed up to observe their pregnancy outcomes.

Statistical analysis

CffDNA testing-positive pregnant women who did not undergo an invasive procedure for confirmation were excluded from the latter analysis. The sensitivity (Sen), specificity (Spe), positive predictive value (PPV), and FPR of cffDNA testing were calculated. SPSS 18.0 software (SPSS Inc., Chicago, IL, USA) was used for data analysis, and the Chi-square test was used for categorical variables. All descriptive data were presented as mean (range), and the count data were described as proportions. P < 0.05 was considered statistically significant.

  Results Top

Study cohort and follow-up

This survey finally enrolled 19,484 pregnant women who underwent cffDNA testing. In our cohort, we identified 208 pregnant women who screened positive, including 57 cases for T21, 18 cases for T18, 7 cases for T13, 106 cases for SCAs, and 20 cases for subchromosomal deletions/duplications [Table 1]. After cffDNA testing, 158 cases (75.96%) underwent subsequent karyotyping and SNP array.
Table 1: Performance of cffDNA testing for screening for fetal chromosome aneuploidy and subchromosomal deletions/duplications

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We followed the women's pregnancy decisions and outcomes. All women with a confirmed normal fetal karyotype (4 as T21, 8 as T18, 4 as T13, 23 as 45, X, 9 as 47, XXX, 9 as 47, XXY, 3 as 47, XYY, and 13 as subchromosomal deletions/duplications) continued their pregnancies and delivered. Forty-eight cases (42 as T21, 5 as T18, and 1 as T13) with fetal T21, T18, and T13 terminated their pregnancies. Only 1 case of T13 was revealed as a true fetal mosaic (TFM) and delivered. As for true fetal SCAs, all 9 cases of 47, XXX and 3 cases with 47, XYY chose to continue the pregnancy and delivered live infants. In the 2 cases of 45, X TFMs, 1 woman terminated the pregnancy and the other chose to continue. The remaining 4 cases of fetal 45, X were terminated, and the same decision was made in 12 of the 13 cases of fetal 47, XXY. Only 1 woman with fetal subchromosomal deletions/duplications terminated the pregnancy, and the other 4 women continued their pregnancies and delivered.

We also followed the pregnancy outcomes of 50 women who rejected prenatal diagnosis, but the neonatal karyotype was not available. Seventeen women who had screen-positive common trisomies (11 as T21, 5 as T18, and 1 as T13) terminated their pregnancies. Ultrasonic abnormalities or embryo growth arrest were observed in 4 cases. Two of 11 cases with 45, X selected to terminate, and the other 9 cases chose to continue and had a live birth. The remaining 22 screen-positive pregnancies (8 as 47, XXX, 8 as 47, XXY, 4 as 47, XXY, and 2 as subchromosomal deletions/duplications) continued gestation. The rate of prenatal diagnosis for cases with screen-positive results of common fetal aneuploidies was higher than for cases with SCAs (79.27% vs. 70.75%).

Clinical performance of cell-free fetal DNA testing for screening fetal chromosomal aneuploidy and subchromosomal deletions/duplications

All cases of T21, T18, and T13 were correctly identified in our study. Of the 158 verification-positive cases, 85 cases were true positives, involving 42 of 46 T21, 5 of 13 T18, 2 of 6 T13, 6 of 29 45, X, 9 of 18 47, XXX, 13 of 22 47, XXY, 3 of 6 47, XYY, and 5 of 18 subchromosomal deletions/duplications, respectively. For the 5 true-positive cases with subchromosomal deletions/duplications, 3 cases were inherited from parents and the other 2 cases occurred due to spontaneous genetic mutations. More details are shown in [Supplementary Table 3]. The overall screen-positive rate was 1.07% (208/19,484). The screen-positive rates for T21, T18, T13, SCAs, and subchromosomal deletions/duplications were 0.29% (57/19,484), 0.09% (18/19,484), 0.04% (7/19,484), 0.54% (106/19,484), and 0.10% (20/19,484), respectively.

We evaluated the performance of cffDNA testing using parameters such as Sen, Spe, PPV, and FPR. The Sen, Spe, PPV, and FPR for the above-mentioned chromosomal abnormalities were 100.00%, 99.62%, 53.80%, and 0.37%, respectively. For combined T21, T18, and T13, the PPV (75.38%) was higher than that for combined SCAs (41.33%) and subchromosomal abnormalities (27.78%; P < 0.05). As for each type of SCA, the PPV was 50.00% (9/18) for 47, XXX, 59.09% (13/22) for 47, XXY, 50.00% (3/6) for 47, XYY, and only 26.09% (6/29) for 45, X. More details about the chromosome abnormalities are given in [Table 1].

Performance of cell-free fetal DNA testing screening for chromosome aneuploidy in high- and low-risk groups

We divided the pregnancies into high-risk (8,758 cases, 44.95%) and low-risk groups (10,726 cases, 55.05%). For this analysis, cffDNA screening-positive cases of fetal subchromosomal deletions/duplications were excluded. [Table 2] shows 188 suspected cffDNA screening-positive cases of chromosome aneuploidies. There was no statistically significant difference in the incidence rate of chromosomal aneuploidies in the high-risk group (1.07%) compared with the low-risk group (0.88%; P > 0.05).
Table 2: Identification of chromosome abnormality in high- and low-risk groups

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Based on karyotyping and follow-up results, the Sen, Spe, PPV, and FPR were 100%, 99.72%, 64.72%, and 0.27% for combined T21, T18, T13, and SCAs in the high-risk group, respectively. For the low-risk group, these parameters were 100%, 99.66%, 50.00%, and 0.34%, respectively. There was no statistically significant difference in cffDNA testing performance for chromosomal aneuploidies between the two groups (Sen, 100.00% vs. 100.00%; Spe, 99.72% vs. 99.66%, P = 0.44; PPV, 64.72% vs. 50.00%, P = 0.079; FPR, 0.27% vs. 0.34%, P = 0.440; [Table 3]).
Table 3: Performance comparison of cffDNA testing between high-risk and low-risk groups

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  Discussion Top

Since 2011, cffDNA testing has been extensively applied in clinical prenatal screening,[23],[24] yet the traditional first-trimester combined test, which is limited to T21, T18, and neural tube defects, is still used in more pregnancies worldwide than cffDNA testing.[25] Previous studies showed that the cffDNA testing has a PPV range of 65%–94% for T21, 47%–85% for T18, and 12%–62% for T13.[26],[27],[28],[29] Our results were comparable to these studies; the PPV was 91.3%, 38.46%, and 33.33%, respectively. For SCAs, the accuracy for predicting sex chromosome trisomies (47, XXX, 47, XXY, and 47, XYY) was higher than for monosomy X, which also had an accuracy similar to that of previous reports.[30],[31] In contrast to pregnant women with fetal T21, T18, and T13, women with a prenatal diagnosis of fetal SCAs were more willing to continue their pregnancy. Among them, women who carrying fetuses with 45, X or 47, XXY were more willing to terminate their pregnancy than women with other fetal SCA types. This difference may be due to the infertility and physical manifestations. In addition, the PPV for monosomy X was much lower. This may be due to these following conditions: (1) confined placental mosaicism; (2) natural loss of the X chromosome; (3) maternal SCA (full or mosaic); (4) co-twin demise; and (5) maternal copy number variants (CNV).[13],[32],[33] Our study population revealed 2 cases of placental mosaicism. Considering the clinical implications and pregnancy decisions in cases that screened positive for SCAs, an explanation of the limitations of cffDNA testing and its clinical anomalies or symptoms is required.[34]

Our results also suggest that cffDNA testing may be useful for screening for subchromosomal deletions/duplications, although the PPV of the current study was only 27.78%. It is worth mentioning that of the 5 true-positive cases, cffDNA testing identified 4 cases with CNVs <3 Mb, 3 of which were inherited from parents. Unfortunately, we found 5 cases of the most prevalent subchromosomal deletions (22q11.2 deletion syndromes) by cffDNA testing in total, while all cases proved to be false-positive results. These data are inconsistent with the latest large-scale study by Liang et al.[35] This discordant result may be due to the small number of suspected 22q11.2 deletion cases we collected.

According to our results, the use of cffDNA testing allowed for the avoidance of approximately 98.65% of unnecessary invasive procedures in high-risk pregnant women. The data by Wald involving 22,812 cases also showed that the use of cffDNA testing allowed women to avoid invasive diagnostic tests as compared with the use of combined serum screening.[36] Furthermore, it should be noted that 36 true-positive cases were identified among low-risk pregnant women in our study. Moreover, the incidence rate was not lower in the low-risk than in the high-risk group. Thus, it is important not to fail to identify chromosomal abnormalities in low-risk pregnancies undergoing cffDNA testing. The data from Manotaya also found screening-positive results in pregnant women with no known risk factors.[37] Despite the proportion of unconfirmed screening-positive results in our study, we showed comparable cffDNA testing performance (Sen, Spe, PPV, and FPR) in screening for common fetal chromosomal abnormalities between the high- and low-risk groups (P > 0.05). To sum up, cffDNA testing can be widely used as a routine prenatal screening method for all pregnant women.

Although with better performance than traditional serum screening for the detection of the common fetal trisomies, cffDNA testing also has limitations. An important factor for the discordant results was the confirmed placental mosaicism. Since cffDNA comes from placental apoptotic fragments, the degree of mosaicism will impact the accuracy. In our study, 47 cases failed mainly because of low fetal fraction. Besides, an increase in weight and BMI had a negative influence on fetal fraction, which might lead to false-negative results. CffDNA testing changed the way we do prenatal screening. However, it can only be recognized as a screening test but not as a diagnostic procedure. All of the screened positive cases should be accurately assessed with noninvasive procedures.

There were several limitations in our study. First, 50 women who screened positive refused to undergo a diagnostic procedure for results validation. Second, the low number of cases of T18, T13, monosomy X, and subchromosomal deletions/duplications may have affected the screening performance. Larger investigations with positive populations could provide better accuracy. Third, false-negative cases remain uncertain because of the absence of neonatal karyotype information, which could affect the FPR and/or negative cases of SCAs.

In summary, our data revealed that cffDNA testing exhibited good screening accuracy for T21, T18, and T13 and also contributed to detecting fetal SCAs and subchromosomal deletions/duplications. The use of cffDNA testing greatly avoided unnecessary invasive diagnostic procedures and can be offered as a routine screening test in the general population in China. We also suggested that the cffDNA testing results could not be used as the direct indication of terminating the pregnancy. It is important for screen positive pregnant women to receive genetic counseling to help them decide whether to continue or terminate their pregnancy.

Supplementary information is linked to the online version of the paper on the Reproductive and Developmental Medicine website.

Financial support and sponsorship

This work was supported by the Shanghai Municipal Health Bureau (grants 20174Y0199 and 201740096) and Shanghai Clinical and Medical Center of Key Programs (2017ZZ01016).

Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3]


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