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Combining Z-Score and Maternal Copy Number Variation Analysis Increases the Positive Rate and Accuracy in Non-Invasive Prenatal Testing.

ABSTRACT: Objective: To evaluate positive rate and accuracy of non-invasive prenatal testing (NIPT) combining Z-score and maternal copy number variation (CNV) analysis. To assess the relationship between Z-score and positive predictive value (PPV). Methods: This prospective study included 61525 pregnancies to determine the correlation between Z-scores and PPV in NIPT, and 3184 pregnancies to perform maternal CNVs analysis. Positive results of NIPT were verified by prenatal diagnosis and/or following-up after birth. Z-score grouping, logistic regression analysis, receiver operating characteristic (ROC) curves, and S-curve trends were applied to correlation analysis of Z-scores and PPV. The maternal CNVs were classified according to the technical standard for the interpretation of ACMG. Through genetic counseling, fetal and maternal phenotypes and family histories were collected. Results: Of the 3184 pregnant women, 22 pregnancies were positive for outlier Z-scores, suggesting fetal aneuploidy. 12 out of 22 pregnancies were true positive (PPV = 54.5%). 17 pregnancies were found maternal pathogenic or likely pathogenic CNVs (> 0.5 Mb) through maternal CNV analysis. Prenatal diagnosis revealed that 7 out of 11 fetuses carried the same CNVs as the mother. Considering the abnormal biochemical indicators during pregnancy and CNV-related clinical phenotypes after birth, two male fetuses without prenatal diagnosis were suspected to carry the maternally-derived CNVs. Further, we identified three CNV-related family histories with variable phenotypes. Statistical analysis of the 61525 pregnancies revealed that Z-scores of chromosomes 21 and 18 were significantly associated with PPV at 3 ≤ Z ≤ 40. Notably, three pregnancies with Z > 40 were both maternal full aneuploidy. At Z < -3, fetuses carried microdeletions instead of monosomies. Sex chromosome trisomy was significantly higher PPV than monosomy. Conclusion: The positive rate of the NIPT screening model combining Z-score and maternal CNV analysis increased from 6.91‰ (22/3184) to 12.25‰ (39/3184) and true positives increased from 12 to 21 pregnancies. We found that this method could improve the positive rate and accuracy of NIPT for aneuploidies and CNVs without increasing testing costs. It provides an early warning for the inheritance of pathogenic CNVs to the next generation.

SUBMITTER: Chen L

PROVIDER: S-EPMC9201951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION:Manganese (Mn) is an essential nutrient but also a toxicant at high exposures, when it can induce oxidative stress (OS). Mn uptake is inversely correlated with iron status, therefore anemic individuals may be more susceptible to Mn overload induced-OS, which can manifest as changes in mitochondrial DNA copy number (mtDNA CN). Our objectives were to: 1) determine stage-specific associations of prenatal Mn exposure with cord blood MtDNA CN; and 2) investigate effect modification by maternal anemia, ferritin, and mean corpuscular volume (MCV). MATERIALS AND METHODS:We measured whole blood Mn, hemoglobin, serum ferritin, and MCV in the 2nd and 3rd trimester, in maternal blood at birth, and in cord blood from a prospective birth cohort in Mexico City, Mexico (n?=?485). We then extracted DNA from cord blood leukocytes to determine mtDNA CN. We used robust regression to measure associations between Mn and mtDNA CN at each trimester and at birth. Anemia (hemoglobin ?11?g/dL), iron deficiency (ferritin ?15?ng/mL) and MCV (stratified at median), were examined as effect modifiers. RESULTS:Mn levels increased throughout pregnancy, and Mn was inversely correlated with ferritin. We observed a positive association between Mn in the 3rd trimester and Mn in cord blood and mtDNA CN (??=?0.04-0.05; 95% CI?=?0.01, 0.08). Anemia significantly modified the association between mtDNA CN and Mn in the 2nd trimester. We found a positive association between 2nd trimester Mn and mtDNA CN in mothers with normal hemoglobin, and a negative association in those with low hemoglobin. (?high?=?0.06; 95% CI?=?0.01, 0.11; p?=?0.01 and ?low?=?-0.06; 95% CI?=?0.03, -0.13; p?=?0.06). No associations were detected between anemia, iron deficiency and MCV and mtDNA CN. CONCLUSIONS:Maternal blood Mn in the 3rd trimester and in cord blood was positively associated with mtDNA CN, suggesting that higher late pregnancy prenatal Mn exposures can impact newborn mitochondria by promoting OS. Furthermore, 2nd trimester Mn was positively associated with mtDNA in non-anemic mother-child pairs but inversely associated in anemic individuals, indicating potential interactions between Mn and chronic anemia.

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Combining Z-Score and Maternal Copy Number Variation Analysis Increases the Positive Rate and Accuracy in Non-Invasive Prenatal Testing.

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