Objectives To report the clinical performance of massively parallel sequencing-based non-invasive prenatal testing (NIPT) in detecting trisomies 21, 18 and 13

Graphical Abstract Highlights d Genome sequencing from low-pass noninvasive prenatal testing samples d GWAS of 141,431 low-pass genomes reveals 16 unknown genetic associations d Patterns of clinically relevant viral infection in maternal plasma d Insights into the genetic structure and history of the Chinese population SUMMARYWe analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses. BLAST Sayers et al., 2009 https://blast.ncbi.nlm.nih.gov/Blast.cgi

BackgroundConventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy.MethodsWe developed an advanced noninvasive prenatal diagnosis method based on massively parallel sequencing. The Noninvasive Fetal Trisomy (NIFTY) test, combines an optimized Student’s t-test with a locally weighted polynomial regression and binary hypotheses. We applied the NIFTY test to 903 pregnancies and compared the diagnostic results with those of full karyotyping.Results16 of 16 trisomy 21, 12 of 12 trisomy 18, two of two trisomy 13, three of four 45, X, one of one XYY and two of two XXY abnormalities were correctly identified. But one false positive case of trisomy 18 and one false negative case of 45, X were observed. The test performed with 100% sensitivity and 99.9% specificity for autosomal aneuploidies and 85.7% sensitivity and 99.9% specificity for sex chromosomal aneuploidies. Compared with three previously reported z-score approaches with/without GC-bias removal and with internal control, the NIFTY test was more accurate and robust for the detection of both autosomal and sex chromosomal aneuploidies in fetuses.ConclusionOur study demonstrates a powerful and reliable methodology for noninvasive prenatal diagnosis.

The fetal fraction was affected by fetal aneuploidy, maternal BMI, and the number of gestation. Maternal preexisting of hypertension appeared to reduce fetal fraction.

With apparently high positive predictive value and low false positive rate, NIPT has the potential to be used as a good alternative approach of conventional prenatal screening at the first trimester in ART twin pregnancy. © 2016 John Wiley & Sons, Ltd.