authored by Valentina Gnetetskaya*
Introduction
Cell-free DNA has been utilized as a novel analyse for the development of non-invasive approaches to prenatal genetic testing using different methodologies [1-4]. Following the publication of a number of major research and clinical studies that revealed high accuracy to detect fetal aneuploidies, the use of noninvasive prenatal testing (NIPT) has been widely adopted in clinical practice. NIPT technologies provide significant improvements over conventional invasive prenatal testing and consequently, international bodies endorse NIPT as a routine screening option [5,6]. This has resulted in many institutions adopting NIPT within the scope of standard of care for autosomal and sex chromosomal aneuploidy detection (SCA). Mother and Child Clinic is a primary clinical centre certified by the Russian Ministry of Health and specialises in screening and diagnosing prenatal chromosomal aneuploidies. NIPT has been offered as a prenatal screening option in our clinic since (May 2017). This study aims to summarize the NIPT results and clinical performance of NIPT in the detection of trisomy 13,18,21 and SCAs using the Veracity non-invasive prenatal test in a cohort of 1382 samples among mixed-risk participants. In this report we convey a complete and robust clinical picture of the performance of Veracity under routine NIPT testing conditions and describe examples of unique clinical cases.
Materials and Methods
Patient cohort
This study included 1382 pregnant women between the ages 18-52 between 9-28 gestational weeks who visited Mother and Child Clinic from May 2017 until October 2018. Of these women 1325 were singleton pregnancies, 37 were twin pregnancies, 20 were vanished twin pregnancies and 169 conceived by in-vitro fertilization including 65 with the use of egg donation. Testing options included detection of trisomy 13,18,21 and optional detection of Sex chromosome aneuploidies (SCAs) and fetal sex. The panel offered for SCAs includes 45X, XXX, XXY, XXYY and XYY constitution. Women provided informed consent and maternal blood (20ml) collected in BCT StreckTubes (Streck, Inc, Omaha, NE) and was sent via courier for testing at the CAP accredited, CLIA certified laboratory of NIPD Genetics Public company Ltd. Sample demographics and outcome information was provided by the clinician and was compiled and reviewed to determine the characteristics of this patient population, as well as estimate the assay performance in our clinical setting.
Pre-test and post-test counselling
Patients were provided with a careful and detailed counselling regarding the benefits, risks and limitations of NIPT testing and provided the relevant consent form. NIPT analysis was conducted immediately for each sample and results were delivered using an electronic web-system within 7 days from sample receipt at NIPD Genetics (Nicosia, Cyprus). Women with a positive NIPT were provided the option of invasive testing. Post-test counselling was given to all participants on the basis of their test results.
Invasive testing
For invasive testing chorionic villus sampling (CVS) or amniocentesis was performed. Comparative genomic hybridization (aCGH) analysis was performed using a customized 60K CGX Chip v2 (Perkin Elmer by Agilent Technologies, Inc, Finland) and the data were analysed by a Genoglyphix aCGH software (PerkinElmer, Finland). Banding cytogenetic was performed using routine techniques on G-banded metaphase chromosomes of CVS or cultured amniotic fluid cells. Centromeric probes were used for FISH analysis. Karyotypes were interpreted according to ISCN.
Results
The median gestational age of this patient cohort (n=1382) was 12+3 weeks (Table 1), and the median maternal age was 34.4 (IQR 7.2) years. The median weight was 61 kg (IQR) (Table 1). The overall distributions of gestational weeks and maternal age are depicted in Figure 1 and Figure 2 respectively. In this cohort twin pregnancy samples represented 2.68% of all referrals (Table 1). In this cohort of 1382 cases, 246 cases requested detection of trisomy’s 13,18 and 21, 47 cases requested detection of trisomy’s 13,18,21 and fetal sex and 1089 cases requested the detection of trisomy’s 13,18,21, fetal sex and SCAs. The detection of SCAs was not an available option in twin pregnancies. In this cohort, 1325 cases were singleton pregnancies, 37 were twin pregnancies and 20 were vanished twin pregnancies. The cohort included 169 pregnancies conceived by in-vitro fertilization out of which 65 were performed with the use of egg donation. In the cohort of twin pregnancies, 23 were dichorionic and 14 were monochorionic. The median fetal fraction of reported samples was 10.2% (Figure 3). The fetal fraction increased as gestational weeks increased and exhibited a weak positive correlation (r= 0.19) (Figure 4).
In this sample cohort 99.5% of samples received a result (1375/1382). 1.9% of samples exhibited insufficient fetal fraction and a redraw was requested (27/1382). Specifically, 27 samples exhibited insufficient fetal fraction of which 22 samples were redrawn and sent to NIPD Genetics laboratories for retesting. Twenty out of 22 samples received a result following re-testing (91%). Overall, the median TAT time for reporting was 5 business days (Table 2).
The incidence of trisomy’s 13,18,21 was 1.6% and the incidence of SCAs was 0.5% (Table 3). In summary, 14 trisomy 21 cases were detected by Veracity NIPT. Follow-up information was available for 13/14 cases and all were confirmed (13/13). Four samples were reported as trisomy 18. Follow-up information was available for all samples and all were confirmed (4/4). One sample was reported as trisomy 13 and was confirmed with follow-up confirmatory testing (1/1). Two cases were reported as 45X with no available confirmatory testing information. One pregnancy loss was reported. One sample was reported as trisomy X and was confirmed with follow-up confirmatory testing (1/1). Two samples were reported as XXY and were confirmed with follow-up confirmatory testing (2/2). One case was reported as XYY with no available follow-up information.
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