Performance of whole-genome promoter nucleosome profiling of maternal plasma cell-free DNA for prenatal noninvasive prediction of fetal macrosomia: a retrospective nested case-control study in mainland China.

BACKGROUND: Fetal macrosomia is common occurrence in pregnancy, which is associated with several adverse prognosis both of maternal and neonatal. While, the accuracy of prediction of fetal macrosomia is poor. The aim of this study was to develop a reliable noninvasive prediction classifier of fetal macrosomia. METHODS: A total of 3600 samples of routine noninvasive prenatal testing (NIPT) data at 12+ 0-27+ 6 weeks of gestation, which were subjected to low-coverage whole-genome sequencing of maternal plasma cell-free DNA (cfDNA), were collected from three independent hospitals. We identified set of genes with significant differential coverages by comparing the promoter profiling between macrosomia cases and controls. We selected genes to develop classifier for noninvasive predicting, by using support vector machine (SVM) and logistic regression models, respectively. The performance of each classifier was evaluated by area under the curve (AUC) analysis. RESULTS: According to the available follow-up results, 162 fetal macrosomia pregnancies and 648 matched controls were included. A total of 1086 genes with significantly differential promoter profiling were found between pregnancies with macrosomia and controls (p < 0.05). With the AUC as a reference，the classifier based on SVM (CMA-A2) had the best performance, with an AUC of 0.8256 (95% CI: 0.7927-0.8586). CONCLUSIONS: Our study provides that assessing the risk of fetal macrosomia by whole-genome promoter nucleosome profiling of maternal plasma cfDNA based on low-coverage next-generation sequencing is feasible.

Whole-Genome Promoter Profiling of Plasma DNA Exhibits Diagnostic Value for Placenta-Origin Pregnancy Complications.

Placenta-origin pregnancy complications, including preeclampsia (PE), gestational diabetes mellitus (GDM), fetal growth restriction (FGR), and macrosomia (MA) are common occurrences in pregnancy, resulting in significant morbidity and mortality for both mother and fetus. However, despite their frequency, there are no reliable methods for the early diagnosis of these complications. Since cfDNA is mainly derived from placental trophoblasts and maternal hematopoietic cells, it might have information for gene expression which can be used for disease prediction. Here, low coverage whole-genome sequencing on plasma DNA from 2,199 pregnancies is performed based on retrospective cohorts of 3,200 pregnant women. Read depth in the promoter regions is examined to define read-depth distribution patterns of promoters for pregnancy complications and controls. Using machine learning methods, classifiers for predicting pregnancy complications are developed. Using these classifiers, complications are successfully predicted with an accuracy of 80.3%, 78.9%, 72.1%, and 83.0% for MA, FGR, GDM, and PE, respectively. The findings suggest that promoter profiling of cfDNA may be used as a biological biomarker for predicting pregnancy complications at early gestational age.