Efficiency of expanded noninvasive prenatal testing in the detection of fetal subchromosomal microdeletion and microduplication in a cohort of 31,256 single pregnancies

Abstract

Noninvasive prenatal testing (NIPT) is widely used to screen for common fetal chromosomal aneuploidies. However, the ability of NIPT-Plus to detect copy number variation (CNV) is debatable. Accordingly, we assessed the efficiency of NIPT-Plus to detect clinically significant fetal CNV. We performed a prospective analysis of 31,260 singleton pregnancies, included from June 2017 to December 2020. Cell-free fetal DNA was directly sequenced using the semiconductor sequencing platform for women with high-risk CNV with clinically significant results. Fetal karyotyping and chromosomal microarray analysis (or next-generation sequencing) are recommended for invasive diagnostic procedures. Women at low risk with no other abnormal results continued their pregnancies. We analyzed the expanded NIPT results, diagnostic test results, and follow-up information to evaluate its performance in detecting fetal CNV. Of the 31,260 pregnant women who received NIPT-Plus, 31,256 cases were tested successfully, a high risk of clinically significant CNV was detected in 221 cases (0.71%); 18 women refused further diagnosis; 203 women underwent invasive prenatal diagnosis; and 78 true positive cases and 125 false positive cases, with an overall positive predictive value (PPV) of 38.42% and a false positive rate of 0.40%. For known microdeletion/microduplication syndromes (n = 27), the PPVs were 75% DiGeorge syndrome (DGS), 80% 22q11.22 microduplication, 50% Prader–Willi syndrome, and 50% cri-du-chat. For the remaining clinically significant fetal CNVs (n = 175), the combined PPVs were 46.5% (CNVs > 10 Mb) and 28.57% (CNVs ≤ 10 Mb). NIPT-Plus screening for CNV has certain clinical value. NIPT-Plus yielded relatively high PPVs for 22q11.2 microduplication syndrome and DGS, and low to moderate PPVs for other CNVs.

Prenatal Screening for Microdeletions and Rare Autosomal Aneuploidies

“…These increased to 100% for CDC and 1p36DS, albeit with extremely small sample sizes, in the setting of ultrasound findings 53 . For the less commonly screened MMS, the PPVs for 22q microduplication and Wolf Hirschhorn were 60% to 80% and 16.7%, respectively 25,55,56,67 .…”

“…The overall screen-positive rate for CNVs, regardless of size or pathogenicity, ranges from 0.1% to 0.9%, with reported sensitivities of 20% to 100% 11,[13][14][15][16][17][18][19][20][22][23][24][25]38,40,[53][54][55][56][57][58][59] .…”

“…Schwartz et al 67 also separately analyzed a cohort of high-risk women with ultrasound anomalies or a family history of microdeletion and reported an increased PPV of 44% versus 7% in the low-risk group. Overall, a large range of PPVs, from 3% to 81%, can be found in the literature 11,[13][14][15][16][17][18][19][20][22][23][24][25]38,40,[53][54][55][56][57][58][59] .…”

“…The overall screen-positive rate for CNVs, regardless of size or pathogenicity, ranges from 0.1% to 0.9%, with reported sensitivities of 20% to 100% 11,13–20,22–25,38,40,53–59 . CNVs have been reported in all chromosomes 23,57,60 .…”

“…Schwartz et al 67 also separately analyzed a cohort of high-risk women with ultrasound anomalies or a family history of microdeletion and reported an increased PPV of 44% versus 7% in the low-risk group. Overall, a large range of PPVs, from 3% to 81%, can be found in the literature 11,13–20,22–25,38,40,53–59 . A 2021 systematic review by Familiari et al, 38 pooled total PPVs from 42 papers with a combined 210 cases of CNVs and calculated a PPV of 44.1%.…”