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Performance of cell-free DNA sequencing-based non-invasive prenatal testing: experience on 36,456 singleton and multiple pregnancies.

ABSTRACT:

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.

SUBMITTER: La Verde M

PROVIDER: S-EPMC8011149 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate the application of non-invasive prenatal testing (NIPT) as an alternative to invasive diagnostic prenatal testing in pregnancies with abnormal ultrasound findings.MethodsThis was a retrospective analysis of 251 singleton and multiple pregnancies at high risk for fetal chromosomal abnormality based on findings at sonographic examination, in which NIPT was performed as a first-tier genetic test. NIPT was performed by massively parallel sequencing of cell-free DNA in maternal plasma, allowing genome-wide detection of whole-chromosome, as well as partial, autosomal aneuploidy. Sex chromosomes were not analyzed, according to the current protocol in Dutch laboratories.ResultsNIPT was performed at a median gestational age of 20 weeks, indicated by the presence of multiple congenital anomalies (n = 13), isolated structural anomalies (n = 57), increased nuchal translucency ≥ 3.5 mm (n = 58), soft markers (n = 73), growth restriction (n = 40) and other anomalies (n = 10). NIPT results were normal in 224 (89.2%) pregnancies, inconclusive in one (0.4%) and abnormal in 26 (10.4%). Most genetic aberrations detected by NIPT were common whole-chromosome aneuploidies: trisomy 21 (n = 13), trisomy 18 (n = 6) and trisomy 13 (n = 3). Four further NIPT results were abnormal; one was suspected of being confined placental mosaicism and one was of maternal origin. In those with normal NIPT results, sonographic follow-up or examination of the newborn indicated the need for diagnostic genetic testing in 33/224 (14.7%) pregnancies. Clinically relevant genetic aberrations were revealed in 7/224 (3.1%) cases, two of which were whole-chromosome aneuploidies: trisomy 13 and monosomy X. As sex chromosomal aberrations are not included in NIPT analysis, the latter cannot be considered a false-negative result. Other discordant findings were subchromosomal aberrations (< 20 megabases, n = 2) and monogenic aberrations (n = 3).ConclusionsNIPT should not be recommended for genetic evaluation of the etiology of ultrasound anomalies, as both resolution and sensitivity, or negative predictive value, are inferior to those of conventional karyotyping and microarray analysis. Nonetheless, some pregnant women consider NIPT to be an acceptable alternative to invasive diagnostic testing. © 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Project description:BackgroundNon-invasive prenatal testing (NIPT) has good screening performance for common chromosomes, but it may have false positive (FP) and false negative (FN) results for various reasons. For abnormal NIPT results, the combination of fetal ultrasound phenotypes will provide more fetal information for prenatal diagnosis. The aim of this study was to combine NIPT and ultrasound phenotypes to analyze their complementary roles in prenatal screening of fetal chromosome abnormalities.MethodsFrom January 2018 to December 2021, 12,803 pregnant women with singleton who successfully underwent NIPT/expanded NIPT (NIPT-Plus) at Xiangya Hospital of Central South University, of which 111 cases were positive results and one case was FN result. We retrospectively collected the clinical features, ultrasonographic findings, prenatal diagnosis, and pregnancy outcomes of these 112 pregnant women and analyzed the ultrasonic manifestations of different chromosomal abnormalities in detail.ResultsThe positive predictive values (PPVs) of NIPT/NIPT-Plus for trisomy (T)21, T18, sex chromosome abnormality (SCA), microdeletion/microduplication syndrome (MMS), T13, and rare autosomal trisomy (RAT) were 100.0%, 85.7%, 57.1%, 44.4%, 40.0%, and 7.7%, respectively. The total termination rates of pregnancy for T21, T18, T13, SCA, pathogenic MMS, and RAT were 93.5%, 100.0%, 100.0%, 66.7%, 100.0%, and 100.0%, respectively. From the karyotypes of SCA live-born fetuses, 47,XYY and 47,XXX were more likely to be selected for continued pregnancy. The ultrasound phenotypes of T21 were diverse, including normal, soft marker, and structural malformation. Both T18 and T13 had structural malformations as the main phenotypes. Most ultrasound phenotypes of FP T21, T18, and T13 were normal but occasionally manifested as fetal growth restriction (FGR). The ultrasound phenotypes of SCA, MMS, and RAT were relatively mild and manifested as normal, soft marker, FGR, or polyhydramnios, and the ultrasound phenotypes were similar between FP and true positive (TP) cases.ConclusionsUltrasound phenotypes are helpful in identifying FP NIPT/NIPT-Plus results, especially for T18 and T13. Given its mild ultrasound phenotypes, NIPT-Plus has important clinical significance in reducing the missed diagnosis of SCA, MMS, and RAT, but its screening performance needs to be further improved.