Clinical evaluation of non-invasive prenatal screening for the detection of fetal genome-wide copy number variants

OBJECTIVE: This study explores and discusses the possible factors affecting the positive predictive value (PPV) of non-invasive prenatal screening (NIPS) for the detection of fetal copy number variants (CNVs) in pregnant women. METHODS: NIPS was performed for 50,972 pregnant women and 212 cases were suspected as fetal CNVs. Post additional genetic counseling for these women, 96 underwent invasive prenatal diagnosis (amniocentesis), following which they received chromosomal microarray analysis (CMA). We analyzed the PPV of NIPS for the detection of fetal CNVs and the possible interference factors that could affect the PPV. RESULTS: Among the 96 pregnant women that received prenatal diagnosis by CMA, 37 cases were confirmed to be true positive for fetal CNVs with a PPV of 38.5%. There was no significant difference between the women with different NIPS indications. Five cases were reported as the false positive and false negative of fetal CNVs and the differences were mainly reflected in the inconsistency of chromosome fragments. Depending on the sizes of the CNVs, the PPVs were 48.7% for CNVs < 3 Mb, 41.4% for CNVs falling within 3 ~ 5 Mb, 42.9% for the CNVs falling within 5 ~ 10 Mb, and 14.3% for CNVs > 10 Mb. Based on the chromosomal locations of CNVs, the PPV(4.8%) of the chromosomes of group C(including chromosomes 6 ~ 12), was lower than that of the other groups (41.2% ~ 66.7%) (p = 0.021). However, there were no significant differences in the CNV characteristics, fetal fractions, unique reads, and the Z-scores between these groups. CONCLUSION: NIPS with a low-coverage sequencing depth has a certain effect on detection of fetal CNVs with the PPV of 38.5%. Chromosomal locations of CNVs may be the main factor that influences its effect. This study can contribute to an increased accuracy in genetic counseling and in predicting NIPS results that are positive for fetal CNVs.