Identification of copy number variations among fetuses with isolated ultrasound soft markers in pregnant women not of advanced maternal age

Abstract

Abstract Background: Pathogenic (P) copy-number variants (CNVs) may be associated with second-trimester ultrasound soft markers (USMs), and non-invasive prenatal screening (NIPS) can enable interrogate the entire fetal genome to screening of fetal CNVs. This study evaluated the clinical application of noninvasive prenatal screening (NIPS) for detecting copy number variants (CNVs) among fetuses with ultrasound soft markers (USMs). Results: Fetal aneuploidies and CNVs were identified using the Berry Genomics NIPS algorithm in 6632 pregnant women. Fetal aneuploidies and CNVs were identified using the Berry Genomics NIPS algorithm. Those with positive NIPS results underwent amniocentesis for prenatal diagnosis. The NIPS and prenatal diagnosis results were analyzed and compared among different USMs. A total of 96 pregnancies were scored positive for fetal chromosome anomalies, comprising 37 aneuploidies and 59 CNVs. Positive predictive values (PPVs) for T21, T18, T13, and sex chromosome aneuploidies were 66.67%, 80.00%, 0%, and 30.43%, respectively. NIPS sensitivity for aneuploidies was 100%. For CNVs, the PPVs were calculated as 35.59% and false positive rate of 0.57%. There were six pathogenic (P) CNVs; two successfully identified by NIPS and four missed, of which three were below the NIPS resolution limit and one false negative. The incidence of aneuploidies was significantly higher in fetuses with absent or hypoplastic nasal bone, while that of P CNVs was significantly higher in fetuses with aberrant right subclavian artery (ARSA), compared with other groups. Conclusions: NIPS yielded a moderate PPV for CNVs in pregnant women with fetal USM. However, NIPS showed limited ability in identifying P CNV. Positive NIPS results for CNV emphasize the need for further prenatal diagnosis. We do not recommend NIPS to screen for CNV in pregnant women with fetal USM, especially in fetuses with ARSA.