Genome-wide detection of additional fetal chromosomal abnormalities by cell-free DNA testing of 15,626 consecutive pregnant women

Abstract

Cell-free DNA (cfDNA) testing for common fetal trisomies (T21, T18, T13) is highly effective. However, the usefulness of cfDNA testing in detecting other chromosomal abnormalities is unclear. We evaluated the performance of cfDNA testing for genome-wide abnormalities, and analyzed the incremental yield by reporting extra abnormalities. We performed genome-wide cfDNA testing in 15,626 consecutive pregnancies prospectively enrolled in this study. cfDNA testing results were reported and counseling was given depending on the presence of extra chromosomal abnormalities. cfDNA testing identified 190 cases (1.2%) of chromosomal abnormalities including 100 common trisomies and 90 additional abnormalities. By expanding the cfDNA reporting range to genome-wide abnormalities, the false positive rate increased to 0.39% (P<0.001) and positive predictive value (PPV) was reduced to 65.58% (P=0.42). However, the detection yield increased from 0.44% to 0.65% (P=0.014), and cfDNA testing detected 38.61% (39/101) additional abnormalities with no ultrasound and biochemical screening findings. cfDNA testing outperformed biochemical screening by showing 60 times higher true positive rate and fewer false negative results. Genome-wide cfDNA testing significantly increased the diagnostic yield by detecting extra abnormalities, especially those without diagnostic indications. Genome-wide cfDNA testing has fewer false positive and false negative results compared with biochemical screening.

Performance of Cell-Free DNA Screening for Fetal Common Aneuploidies and Sex Chromosomal Abnormalities: A Prospective Study from a Less Developed Autonomous Region in Mainland China

“…The combined PPV, NPV and FPR for these additional abnormalities were 23.21%, 99.98% and 0.05%, respectively. In total, when NIPS detection scope were expanded from common trisomies and SCAs to genome-wide abnormalities (CNVs and RATs), the combined PPV was only slightly decreased from 64.43% to 62.08%, and the FPR was also slightly increased from 0.40 to 0.45% (Table 3), both of which were similar to a previous study [12].…”

“…The positive rate of such abnormalities by expanded NIPS ranged from 0.12 to 1.58% among all submitted cases [7,8,[10][11][12][13], with the positive predictive values (PPVs) for copy number variants (CNVs), RATs and other abnormalities as 28.99-57.14% [8,10,12,13], 6-58.82% [8,10,13,14] and 0-64% [10][11][12], respectively. Although expanded NIPS is able to provide an increased yield of the overall chromosomal abnormalities [8], it is still difficult to evaluate its sensitivity and specificity due to the differences exist in (1) types and spectrum of chromosomal abnormalities, (2) resolution (sizes) [13,15,16], (3) sequencing platforms [8,17], (4) sequencing parameters analyzed (such as sequencing read-depth and cf-DNA%) [17,18] and (5) referral indications [12,16,19,20]. In addition, as the incidence of individual aberration is low, validation in a cohort with large sample size with pregnancy outcomes is challenging but still needed.…”

“…However, most of the published data from China were collected from different centers. Due to the small sample size without follow-up data, the number of different types of abnormalities from each single center was insufficient for comparison [8,10,12], or represent the general population. Moreover, the utility of expanded NIPS in the general obstetric population is still on debate.…”

Benefit vs potential harm of genome‐wide prenatal cfDNA testing requires further investigation and should not be dismissed based on current data

“…Indeed, not all fetal anomalies can be detected by prenatal ultrasound, especially not at an equally early gestational age. A previous study has shown that 38.6% of the cases with additional findings detected via cfDNA testing in a cohort of 15 626 consecutive pregnancies had no ultrasound anomalies. Lastly, Jani et al .…”

Disorder of Sexual Development Males With XYY in Blood Have Exactly X/XY/XYY Mosaicism in Gonad Tissues

“…The diagnosis of chromosome diseases is highly dependent on GTG-binding of blood samples. The 47,XYY syndrome is a common sex chromosome aneuploidy that occurs in 1 out of 1,000 male births (Bardsley et al, 2013;Gao et al, 2014;Jo et al, 2016;Yao et al, 2019). Although XYY is diagnosed routinely through GTG-banding of peripheral blood, the phenotypes of XYY patients may vary greatly, ranging from no phenotype and relatively few abnormalities to multi-systemic symptoms; for a specific symptom, the severity can vary among individuals (Kim et al, 2013;Bardsley et al, 2013).Some scholars believe that XYY is associated with a status of over-masculinization, because the existence of an extra Y chromosome and XYY individuals usually results in tall stature, impulsivity, and/or sex organ overdevelopment (macroorchidism and macropenis) (Bardsley et al, 2013;Jo et al, 2015).…”