Massively Parallel Sequencing of Maternal Plasma DNA in 113 Cases of Fetal Nuchal Cystic Hygroma

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Abstract
To estimate the accuracy and potential clinical effect of using massively parallel sequencing of maternal plasma DNA to detect fetal aneuploidy in a cohort of pregnant women carrying fetuses with nuchal cystic hygroma. The MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) study database was queried to identify eligible patients carrying fetuses with cystic hygroma (n=113) based on clinical ultrasonographic examination reports near enrollment. Archived plasma samples were newly sequenced and normalized chromosome values were determined. Aneuploidy classifications for chromosomes 21, 18, 13, and X were made using the massively parallel sequencing data by laboratory personnel blinded to fetal karyotype and compared for analysis. Sixty-nine of 113 (61%) patients had fetuses with abnormal karyotypes, including trisomy 21 (n=30), monosomy X (n=21), trisomy 18 (n=10), trisomy 13 (n=4), and other (n=4). There were 44 euploid cases; none was called positive for aneuploidy. The massively parallel sequencing detection rates were as follows: T21: 30 of 30, T18: 10 of 10, T13: three of four, and monosomy X: 20 of 21, including two complex mosaic cases. Overall, using massively parallel sequencing results of the four studied chromosomes, 107 of 113 (95%, 95% confidence interval [CI] 88.8–98.0) cases were accurately called by massively parallel sequencing, including 63 of 65 (97%, 95% CI 89.3–99.6) of cases of whole chromosome aneuploidy. Massively parallel sequencing provides an accurate way of detecting the most prevalent aneuploidies associated with cystic hygroma. Massively parallel sequencing could advance prenatal care by providing alternative point-of-care noninvasive testing for pregnant women who either decline or do not have access to an invasive procedure. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01122524. II