Shotgun next-generation sequencing of maternal plasma: a method for prenatal aneuploidy identification

PURPOSE: Every year, thousands of Americans pursue prenatal diagnosis of fetal aneuploidy though chorionic villus sampling (CVS) or amniocentesis. Because these procedures are invasive and carry an inherent risk for pregnancy loss, they are selectively offered to women who have an increased risk to have a child with a chromosome condition, such as aneuploidy. In order to identify pregnancies at an increased risk, several non-invasive screening methods have been developed. Although quite useful, these screening methods have limited accuracy and can only be completed during specific gestational age windows. Recent discovery of cell free fetal DNA in maternal circulation has created new and exciting possibilities for prenatal screening and non-invasive prenatal diagnosis. This research study explores shotgun next-generation sequencing of fetal DNA in maternal plasma as a method for non-invasive identification of fetal aneuploidy.METHODS: We carried out shotgun next-generation sequencing on samples of maternal plasma DNA obtained in the first trimester of pregnancies with confirmed aneuploidy and control pregnancies. Three Trisomy 21 samples were compared to four control samples in order to identify any differences in the amount of chromosomal material. RESULTS: We identified a statistically significant increase in chromosome 21 material in the cases of Trisomy 21 as compared to the control cases.IMPLICATIONS: This research demonstrates that shotgun next-generation sequencing of maternal plasma DNA can successfully identify Trisomy 21, showing that it is possible to detect fetal aneuploidy using this noninvasive method. This technology could potentially be used as a method of noninvasive screening for fetal aneuploidy, which is likely to have improved accuracy over other screening methods. Development of a screening test with greater sensitivity and specificity could have significant public health implications. This would not only provide more accurate identification of pregnancies at an increased risk for aneuploidy, but it would also reduce the number of false positives. This in turn would reduce the number of pregnancies that are unnecessarily classified as "high risk", preventing avoidable parental anxiety and reducing the number of pregnancies that are put at unnecessary risk of invasive prenatal diagnostic procedures