Elevated levels of total (maternal and fetal) β-globin DNA in maternal blood from first trimester pregnancies with trisomy 21

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BACKGROUND: Elevated levels of circulating fetal DNA have been observed in maternal plasma when a trisomy 21 fetus is confirmed. However, these studies have been limited to pregnancies carrying a male fetus. We sought to quantify total (fetal and maternal) DNA from dried blood spots (DBS) for use as an additional factor in multi-parameter prenatal screening for aneuploidy. METHODS: Maternal DBS were obtained from the NICHD-sponsored multi-center cohort (BUN) study. Seventeen confirmed trisomy 21 (mean gestational age 12.23 +/- 0.77 weeks) cases were each matched by gestational age to euploid controls (n = 30). DNA was extracted and quantitative PCR was performed to measure four non-chromosome 21 loci, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (12p13), beta-globin (11p15.5), beta-actin (7p15-12) and p53 (17p13.1). RESULTS: Beta-globin DNA levels were significantly elevated (P = 0.003) in 13 of 17 trisomy 21 cases (4.08 +/- 1.78 Geq/ml x 10(5)) compared with matched controls (2.35 +/- 1.84 Geq/ml x 10(5)). Following conversion of beta-globin concentrations into multiples of the median (MoM), MoM for trisomy 21 cases was 2.8 compared with 1.0 in euploid cases. No significant differences in levels of circulating GAPDH, beta-actin and p53 sequences were detected. CONCLUSIONS: This work demonstrates differential levels of circulating beta-globin DNA in maternal blood of euploid and trisomy 21 cases. Sequence-specific quantification could provide an additional measure to improve non-invasive methods of prenatal screening to detect trisomy 21 using dried blood. Beta-globin in particular is an attractive biomarker that could contribute to enhance multiple serum parameter testing in the first trimester.