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Relationship between fetal fraction and RAAs per chromosome. The box plots represent the first and third quartile (upper and lower margins of the box, respectively), the minimum and maximum FF values (lower and upper whiskers, respectively), the median FF (horizontal line within the box), and the mean FF (X within the box). The dots are outliers.
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Cell-free (cf) DNA screening is a noninvasive prenatal screening approach that is typically used to screen for common fetal trisomies, with optional screening for sex chromosomal aneuploidies and fetal sex. Genome-wide cfDNA screening can screen for a wide variety of additional anomalies, including rare autosomal aneuploidies (RAAs) and copy number...
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First-trimester septated cystic hygroma occurs in approximately 1 in 268 pregnancies and has long been associated with a markedly increased risk of fetal aneuploidy and, among euploid fetuses, an increased risk of structural anomalies primarily affecting the cardiac and skeletal systems. Invasive prenatal diagnosis - chorionic villus sampling and/o...
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... In recent years, the scope of prenatal cfDNA screening has expanded to include optional screening for rare autosomal aneuploidies (RAAs) and copy-number variations (CNVs). Recent publications have reported their clinical experience with screening for these rarer chromosomal abnormalities [8][9][10][11][12][13][14][15], and some of them observed that these additional findings were related to perinatal outcomes. Harasim et al. found that half of their RAA cases had signs of either placental insufficiency or intrauterine death [8]. ...
... They also found that prenatal cfDNA screening for CNVs enabled the detection of unbalanced translocations and relevant maternal health conditions. Mossfield et al. showed that many of their patients had adverse pregnancy outcomes, including fetal growth restriction (FGR), intrauterine fetal demise, and preterm birth, when RAAs were detected [9]. Moreover, the TRIDENT study in the Netherlands found that most of these additional findings had a clinical impact [15]. ...
... The most common RAAs in our cohort were trisomy 7 and trisomy 16. Trisomy 7 is the most frequently detected RAA in other genome-wide cfDNA screening studies [9,14,18,23,25], and trisomy 16 is thought to be the most common RAA in adverse pregnancy outcomes [15,26]. Our calculated PPV for RAAs was 10.7%, which is similar to the 11.46% pooled PPV noted in a recent meta-analysis of studies with rare autosomal trisomies [27]. ...
Genome-wide prenatal cell-free DNA (cfDNA) screening can be used to screen for a wide range of fetal chromosomal anomalies in pregnant patients. In this study, we describe our clinical experience with a genome-wide cfDNA assay in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RAAs), and copy-number variations (CNVs) in about 6000 patients over a three-year period at our hospital’s Prenatal Diagnostic Unit in Spain. Overall, 204 (3.3%) patients had a high-risk call, which included 76 trisomy 21, 21 trisomy 18, 7 trisomy 13, 29 SCAs, 31 RAAs, 31 CNVs, and 9 cases with multiple anomalies. The diagnostic outcomes were obtained for the high-risk cases when available, allowing for the calculation of positive predictive values (PPVs). Calculated PPVs were 95.9% for trisomy 21, 77.8% for trisomy 18, 66.7% for trisomy 13, 10.7% for RAAs, and 10.7% for CNVs. Pregnancy and birth outcomes were also collected for the majority of RAA and CNV cases. Adverse perinatal outcomes for some of these cases included preeclampsia, fetal growth restriction, preterm birth, reduced birth weight, and major congenital structural abnormalities. In conclusion, our study showed strong performance for genome-wide cfDNA screening in a large cohort of pregnancy patients in Spain.
... Genome-wide cfDNA screening can identify chromosomal aneuploidies that may impact a pregnancy beyond trisomies 21, 18, and 13, including rare autosomal aneuploidies (RAAs) and copy number variants. There has been an increasing number of studies detailing their clinical experience with genome-wide cfDNA screening in recent years [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Several of these studies have also detailed the adverse perinatal complications that can arise in some patients that screen-positive for RAAs or copy number variants following genome-wide cfDNA screening including preeclampsia, fetal growth restriction, intrauterine fetal demise, and preterm birth. ...
... Studies have shown screen-positive rates for RAAs ranging from 0.12 to 1.1% [23,27]. In our previous study looking at the impact of RAAs on pregnancy management and outcomes, we found that trisomy 20 was detected in 9.2% of patients with a screen-positive result for a RAA [12]. Another recent study noted that trisomy 20 was one of the most frequent rare autosomal trisomies in their patient cohort (11.5% of screen-positive cases) [18]. ...
... The objective of this study was to add to the body of evidence around prenatal screening for conditions beyond the common trisomies by describing the outcomes of a small cohort of patients that had a positive result for trisomy 20 following genome-wide cfDNA screening. These cases were previously published as part of a larger cohort of cases [12]. Diagnostic testing outcomes as well as pregnancy and birth outcomes for these cases are discussed. ...
Trisomy 20 has been shown to be one of the most frequent rare autosomal trisomies in patients that undergo genome-wide noninvasive prenatal testing. Here, we describe the clinical outcomes of cases that screened positive for trisomy 20 following prenatal genome-wide cell-free (cf.) DNA screening. These cases are part of a larger cohort of previously published cases. Members of the Global Expanded NIPT Consortium were invited to submit details on their cases with a single rare autosomal aneuploidy following genome-wide cfDNA screening for retrospective analysis. Clinical details including patient demographics, test indications, diagnostic testing, and obstetric pregnancy outcomes were collected. Genome-wide cfDNA screening was conducted following site-specific laboratory procedures. Cases which screened positive for trisomy 20 (n = 10) were reviewed. Clinical outcome information was available for 90% (9/10) of our screen-positive trisomy 20 cases; the case without diagnostic testing ended in a fetal demise. Of the nine cases with outcome information, one was found to have a mosaic partial duplication (duplication at 20p13), rather than a full trisomy 20. Only one case in the study cohort had placental testing; therefore, confined placental mosaicism could not be ruled out in most cases. Adverse pregnancy outcomes were seen in half of the cases, which could suggest the presence of underlying confined placental mosaicism or mosaic/full fetal trisomy 20. Based on our limited series, the likelihood of true fetal aneuploidy is low but pregnancies may be at increased risk for adverse obstetric outcomes and may benefit from additional surveillance.
... However, studies that investigated the clinical relevance of these additional findings from whole-genome sequencing-based NIPT are limited. A recent publication showed that genome-wide aneuploidy screening for the presence of rare autosomal aneuploidies could be beneficial in a number of clinical situations, such as providing a possible explanation for an adverse pregnancy outcome or resulting in a change in pregnancy management [24]. ...
... However, a repeat NIPS at a later gestational age returned a lowrisk result, again suggesting that the demised twin was affected. Similar results were noted in a recent study by Mossfield et al. [24], in which four cases of a co-twin demise returned normal NIPS results upon a repeat blood draw carried out at a later gestational age. In that study, the authors suggested that the RAA result on the NIPS may have been attributed to the demised twin and that this may provide an explanation to the patient for the loss of that twin. ...
... However, without additional information, we are unable to provide an explanation for this discordant NIPS result. Some recent publications looking at genome-wide NIPS have noted that concordance of RAA results can be based on either fetal or placental testing or both [13,24]. This is mainly due to the fact that RAAs are often found to be present in placental tissues only, i.e., confined placental mosaicism (CPM). ...
Non-invasive prenatal screening (NIPS) in twin gestations has been shown to have high detection rates and low false-positive rates for trisomy 21, as seen in singleton pregnancies, although there have been few large cohort twin studies, genome-wide studies in particular, to date. In this study, we looked at the performance of genome-wide NIPT in a large cohort consisting of 1244 twin pregnancy samples collected over a two-year period in a single laboratory in Italy. All samples underwent an NIPS for common trisomies, with 61.5% of study participants choosing to undergo genome-wide NIPS for additional fetal anomalies (namely, rare autosomal aneuploidies and CNVs). There were nine initial no-call results, all of which were resolved upon retest. Based on our NIPS results, 17 samples were at high risk for trisomy 21, one for trisomy 18, six for a rare autosomal aneuploidy, and four for a CNV. Clinical follow-up was available for 27 out of 29 high-risk cases; a sensitivity of 100%, a specificity of 99.9%, and a PPV of 94.4% were noted for trisomy 21. Clinical follow-up was also available for 1110 (96.6%) of the low-risk cases, all of which were true negatives. In conclusion, we found that NIPS was a reliable screening approach for trisomy 21 in twin pregnancies.
... The detection rates for trisomy 21 typically exceed 99% with low false-positive (FP) rates, <0.1%, [3] and rare false-negative (FN) cases reported in large clinical studies [4][5][6]. In recent years, the use of cfDNA to screen chromosome alterations has been expanded to genome-wide screening for rare autosomal aneuploidies (RAAs) and partial deletions and duplications (i.e., copy number variants, including selected microdeletions), and an increasing number of studies have described the test performance and the clinical validity of these additional fetal anomalies [7][8][9][10][11]. A recent study that looked at diagnostic outcomes for CNV cases identified by genome-wide NIPT found an overall PPV of >70% [12], while in another study a positive predictive value (PPV) of 22.4% for RAA was reported in a large cohort [9]. ...
Non-invasive prenatal testing (NIPT) using cell-free DNA can detect fetal chromosomal anomalies with high clinical sensitivity and specificity. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant. Here we report a case of a 32-year-old pregnant patient with a 44.1 Mb duplication on the short arm of chromosome 4 detected by NIPT at 12 weeks’ gestation. Amniocentesis was carried out at 18 weeks’ gestation, followed by conventional and molecular cytogenetic analysis on cells from the amniotic fluid. SNP array analysis found a de novo deletion of 1.2 Mb at chromosome 4, and this deletion was found to be near the critical region of the Wolf-Hirschhorn syndrome. A normal 46,XY karyotype was identified by G-banding analysis. The patient underwent an elective termination and molecular investigations on tissues from the fetus, and the placenta confirmed the presence of type VI true fetal mosaicism. It is important that a patient receives counselling following a high-risk call on NIPT, with appropriate diagnostic analysis advised before any decisions regarding the pregnancy are taken. This case highlights the importance of genetic counselling following a high-risk call on NIPT, especially in light of the increasing capabilities of NIPT detection of sub-chromosomal deletions and duplications.
... Although the RAT rate is relatively low, pregnancies identified as high risk for RAT using NIPT showed poorer outcomes, such as phenotypic abnormalities, growth restriction, preterm birth, and low birth weight, in addition to increased fetal loss and a higher rate of adverse outcomes, including neurodevelopmental delay and malformations [29][30][31][32][33][34]. ...
Rare autosomal trisomies (RATs) other than common aneuploidies can be detected using noninvasive prenatal testing (NIPT). However, conventional karyotyping is insufficient for evaluating diploid fetuses with uniparental disomy (UPD) due to trisomy rescue. Using the diagnostic process for Prader–Willi syndrome (PWS), we aim to describe the need for additional prenatal diagnostic testing for confirming UPD in fetuses diagnosed with RATs via NIPT and its clinical implications. NIPT was performed using the massively parallel sequencing (MPS) method, and all pregnant women with RATs underwent amniocentesis. After confirming the normal karyotype, short tandem repeat (STR) analysis, methylation-specific PCR (MS-PCR), and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were performed to detect UPD. Overall, six cases were diagnosed with RATs. There was a suspicion of trisomies of chromosomes 7, 8, and 15 in two cases each. However, these cases were confirmed to have a normal karyotype using amniocentesis. In one of six cases, PWS caused by maternal UPD 15 was diagnosed using MS-PCR and MS-MLPA. We propose that in cases where RAT is detected by NIPT, UPD should be considered following trisomy rescue. Even if amniocentesis confirms a normal karyotype, UPD testing (such as MS-PCR and MS-MLPA) should be recommended for accurate assessment, as an accurate diagnosis can lead to appropriate genetic counseling and improved overall pregnancy management.
Introduction: Noninvasive prenatal testing (NIPT) using cell-free DNA (cfDNA) is typically carried out to screen for common fetal chromosomal anomalies, with the option to screen for a wider range of chromosomal changes (expanded NIPT) becoming increasingly available. However, little is known about pregnant patients’ attitudes and preferences regarding expanded NIPT.
Methods: To address this gap, we surveyed general-risk patients having first-tier cfDNA screening at a private prenatal clinic on their expectations for expanded NIPT. Patients were asked questions regarding their current pregnancy and previous pregnancy history, their opinions on fetal DNA screenings during pregnancy and incidental findings, information and opinions on financial resources for NIPT, as well as socio-cultural questions to determine patient demographics.
Results: Of the 200 survey participants, the majority were educated, self-reported as white, had a higher than average income, and reported no aneuploidy risk factors. When asked what information they would like to receive from cfDNA screening, the vast majority of participants wanted all information available that could have an immediate impact on fetal health (88%) or an immediate impact on infant health from birth (82%). Many participants also wanted information that could have a future impact on the child’s health or an immediate or future impact on the pregnant woman’s own health. Most participants wanted information about the sex of fetus (86%) and common trisomies (71%), with almost half of participants desiring information about rare autosomal aneuploidies and/or all genetic information that may affect the baby. In addition, participants were found to be comfortable screening for conditions that are well-known, influence care during pregnancy, and are treatable. Finally, while most respondents either had insurance coverage for NIPT or were able to afford NIPT out of pocket, the majority of our participants felt that expanded NIPT should be either free for everyone or for those considered high risk.
Discussion: Our findings suggest that with appropriate pre-test counseling, pregnant patients may choose NIPT for an expanding list of conditions.
