Noninvasive prenatal testing for fetal subchromosomal copy number variations and chromosomal aneuploidy by low‐pass whole‐genome sequencing

Abstract

Background Expanding noninvasive prenatal testing (NIPT) to include the detection of fetal subchromosomal copy number variations (CNVs) significantly decreased the sensitivity and specificity. Developing analytic pipeline to achieve high performance in the noninvasive detection of CNVs will largely contribute to the application of CNVs screening in clinical practice. Methods We developed the Noninvasively Prenatal Subchromosomal Copy number variation Detection (NIPSCCD) method based on low‐pass whole‐genome sequencing, and evaluated its efficacy in detecting fetal CNVs and chromosomal aneuploidies with 20,003 pregnant women. Results Totally, NIPSCCD identified 36 CNVs, including 29 CNVs consistent and 7 CNVs inconsistent with amniocytes tests. Additionally, seven fetal CNVs identified by amniocytes testing were undetected by NIPSCCD. The sensitivities for detecting CNVs > 10 Mb, 5 Mb–10 Mb, and CNVs < 5 Mb were 91.67%, 100.00%, and 68.42%, respectively. Moreover, NIPSCCD identified 103/ true positive trisomy 21/18/13 cases and 21 false positives, producing an overall 100.00% sensitivity and 99.89% specificity. Conclusion NIPSCCD showed a good performance in detecting fetal subchromosomal CNVs, especially for CNVs >10 Mb, and can be incorporated into the routine NIPT chromosomal aneuploidies screening with high sensitivity and specificity.

Validation of Copy Number Variants Detection from Pregnant Plasma Using Low-Pass Whole-Genome Sequencing in Noninvasive Prenatal Testing-Like Settings

“…As indicated above, it should be noted that our detection pipeline is capable of differentiating between a fetal CNV and a CNV from the mother (or the mother and the fetus). In a prospective setting, we noticed that very small aberrations are often calculated into the overall sensitivity [ 11 , 23 ] without evaluation of the z-score for the given aberration. We, therefore, assume that they would have been missed if they had not been maternal.…”

“…Yu et al employed a Non-Invasively Prenatal Sub-Chromosomal Copy number variation Detection (NIPSCCD) algorithm and evaluated its performance on more than 20,000 clinical samples. The team achieved more than 90% sensitivity for CNVs of 5 Mb–10 Mb and 100% sensitivity for those ≥ 10 Mb with an average of 7.5 M sequencing tags [ 11 ]. Straver et al showed that 71.8% of CNVs ranging from 0.52 Mb to 84 Mb could be detected with as little as 3.5 M tags using the algorithm titled WISECONDOR (WIthinSamplE COpy Number aberration DetectOR), but with lower sensitivity (41.2% between 1 Mb and 5 Mb) [ 12 ].…”

Prenatal diagnosis of a de novo trisomy 20p detected by noninvasive prenatal testing

“…The common use of next-generation sequencing (NGS) and array comparative genomic hybridization (aCGH) in diagnostics has led to an increase of known pathogenic CNVs 10 . Thanks to the application of NIPT, fetal chromosomal aneuploidies subchromosomal abnormalities can be screening with high sensitivity and specificity 11,12 .…”

Detection of a rare de novo 18p terminal deletion with inverted duplication in a Chinese pregnant woman

“…NIPT screening was performed as previous reported (Yu et al, ) at 17 weeks of gestation using the noninvasive prenatal subchromosomal copy number variation detection (NIPSCCD) method, which was low‐pass whole‐genome sequencing based approach.…”