Research Article: An efficient method for noninvasive prenatal diagnosis of fetal trisomy 13, trisomy 18, and trisomy 21

Date Published: April 12, 2019

Publisher: Public Library of Science

Author(s): Xiaohan Sun, Jianbo Lu, Xu Ma, Maurizio D’Esposito.


Molecular size determination of circulating free fetal DNA in maternal plasma is an important detection method for noninvasive prenatal testing (NIPT). The fetal DNA molecule is the primary factor determining the overall performance of NIPT and its clinical interpretation. The proportion of cell-free fetal DNA molecules is expressed as the fetal DNA fraction in the plasma of pregnant women.

We proposed an effective method to deduce fetal chromosomal aneuploidy based on the proportion of a certain range of DNA fragment lengths from maternal plasma. We gradually narrowed the range of the upper and lower boundary via a traversing algorithm.

We explored the optimal range of the upper and lower boundary by using size-based DNA fragment length. Using this range, the accuracy of the sensitivity and specificity could be improved by up to 100% for detecting the three most common autosomal aneuploidies, namely trisomy 13, trisomy 18, trisomy 21 in the sample set.

Numerical experiments demonstrate that our method is effective and efficient. The program is available upon request.

Partial Text

Noninvasive prenatal testing (NIPT) is now widely used in clinical practices worldwide and does not require traumatic sampling, with high accuracy, high sensitivity and specificity. For most pregnant women, the invasive sampling of fetal genetic material through amniocentesis or chorionic villus sampling is gradually replaced by noninvasive prenatal testing [1,2]. NIPT can screen for fetal chromosome aneuploidy and certain copy number variations [2]. In 1997, Dennis Lo found that cell-free fetal DNA (cffDNA) was present in the maternal plasma and it increased stably with the gestational weeks and disappeared rapidly with the delivery of pregnant women, which can be used as an ideal material for NIPT [3]. The cffDNA was discovered in plasma of pregnant women in 1997 which developed a new technique to analyze and measure accurately fetal DNA in maternal plasma [3].

One sample set was applied which had been used in previous studies [2,4–5]. There were 144 maternal plasma sample cases, which were divided into four parts in the sample set. These included 21 cases each with a trisomy 13 fetus, 27 cases each with a trisomy 18 fetus, 36 cases each with a trisomy 21 fetus, and 60 cases each with a euploid fetus. None of the pregnancy samples collected were tested for any invasive sampling of fetal genetic material [5]. The sample set we used came from “Size-based molecular diagnostics using plasma DNA for noninvasive prenatal testing”, contributed by Y. M. Dennis Lo, April 2, 2014, PNAS. USA. The data information is shown in S1 Dataset.

In the study, we calculated the proportions of all 24 chromosomes by observation and comparison. In general, the ratio of each chromosome from sequencing samples tends to be consistent. When a fetus had autosome aneuploidy, its corresponding chromosome ratio would increase. We know that if there are extra or missing chromosomes, the number of corresponding fetal DNA fragments will increase or decrease [24–26]. For instance, the proportion of chromosome 21 in a sample from a pregnant woman carrying a trisomy 21 fetus is higher than in a normal maternal plasma sample [27]. We can use this principle to predict multiple chromosome diseases. This method we used is simple and effective, and can be used as a first-tier screening test to determine multiple types of fetal autosomal aneuploidies.

In conclusion, numerical experiments demonstrate that our method is effective and efficient. Research into the size range of cell-free fetal DNA fragments is important for the performance of NIPT and its clinical assessment. This study suggests that most of the cell-free fetal DNA fragments are between 80 and 155 bp in length, which may serve as a valuable reference point for future research. The results of sample collection and processing are supplemented S1 Files.




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