Abstract
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.
Highlights
Conventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy
Conventional prenatal diagnostic methods for detecting aneuploidies, such as karyotyping, FISH and QF-polymerase chain reaction (PCR), which rely on invasive procedures, bear potential risks for miscarriage [9,10]
We developed an advanced GC-correlation methodology for an massively parallel sequencing (MPS)-based, noninvasive fetal trisomy (NIFTY) test
Summary
Conventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy. The fraction of fetal DNA in the maternal plasma varies from 5% to 10%, which makes it difficult to detect genetic variation in the fetus [17,18]. Conventional molecular techniques, such as allele-specific polymerase chain reaction (PCR) or quantitative real-time PCR, which aim to detect fetal chromosomal disorders, focus only on specific populations [19,20,21], such as fetuses with heterozygous alleles. Several recent studies demonstrated that fetal aneuploidies could be detected and quantified via high-throughput whole-genome sequencing of maternal plasma cell-free DNA combined with a standard z-score test. Prior studies by Chiu et al and Ehrich et al suggest that an MPS-based approach is reliable at detecting trisomy 21 [25,26]
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