Xiaolin Shi1, Zhitao Zhang1, David S Cram2, Caixia Liu3. 1. Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. 2. Berry Genomics, Beijing. Electronic address: david.cram@berrygenomics.com. 3. Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. Electronic address: liucx1716@163.com.
Abstract
BACKGROUND: Noninvasive prenatal testing (NIPT) by massively parallel sequencing (MPS) of the circulating cell free fetal (cff) DNA during the second trimester of pregnancy is now a frontline test for detecting common fetal chromosomal abnormalities. However, the availability of an earlier test result in the first trimester would enable better clinical management of high-risk pregnancies. The aim of the study was to determine the feasibility of early gestational NIPT. METHODS: Plasma DNA libraries were subjected to MPS and chromosomal read counts normalized to reference. Chromosomal aneuploidy was determined by z-scores (-3<z<3, normal range). The cff DNA fraction in 96 male pregnancies was calculated by the relative proportion of Y chromosomal reads. RESULTS: NIPT results were obtained in the first (8-12 weeks) and second (15-18 weeks) trimester for 182 high-risk women. NIPT identified T21, T13 and 45,X in 3 pregnancies that were confirmed by karyotyping, but missed a T15 pregnancy that eventually miscarried. In the remaining 178 pregnancies, results for first and second trimester NIPT were normal. The median fetal fraction in the first trimester was 7.6 ± 4.18% and 15% of samples were identified with a cff fraction below 4%. Different trends of cff DNA fraction change were observed between the first and second trimester, with 59% of pregnancies showing an increase, 17% showing no change and 24% showing a decrease. CONCLUSIONS: Although NIPT was highly reliable and accurate at an earlier gestational age, clinical implementation should proceed with caution due to a small, but significant, number of pregnancies associated with a low cff DNA fraction.
BACKGROUND: Noninvasive prenatal testing (NIPT) by massively parallel sequencing (MPS) of the circulating cell free fetal (cff) DNA during the second trimester of pregnancy is now a frontline test for detecting common fetal chromosomal abnormalities. However, the availability of an earlier test result in the first trimester would enable better clinical management of high-risk pregnancies. The aim of the study was to determine the feasibility of early gestational NIPT. METHODS: Plasma DNA libraries were subjected to MPS and chromosomal read counts normalized to reference. Chromosomal aneuploidy was determined by z-scores (-3<z<3, normal range). The cff DNA fraction in 96 male pregnancies was calculated by the relative proportion of Y chromosomal reads. RESULTS: NIPT results were obtained in the first (8-12 weeks) and second (15-18 weeks) trimester for 182 high-risk women. NIPT identified T21, T13 and 45,X in 3 pregnancies that were confirmed by karyotyping, but missed a T15 pregnancy that eventually miscarried. In the remaining 178 pregnancies, results for first and second trimester NIPT were normal. The median fetal fraction in the first trimester was 7.6 ± 4.18% and 15% of samples were identified with a cff fraction below 4%. Different trends of cff DNA fraction change were observed between the first and second trimester, with 59% of pregnancies showing an increase, 17% showing no change and 24% showing a decrease. CONCLUSIONS: Although NIPT was highly reliable and accurate at an earlier gestational age, clinical implementation should proceed with caution due to a small, but significant, number of pregnancies associated with a low cff DNA fraction.
Authors: Carlo Vermeulen; Geert Geeven; Elzo de Wit; Marjon J A M Verstegen; Rumo P M Jansen; Melissa van Kranenburg; Ewart de Bruijn; Sara L Pulit; Evelien Kruisselbrink; Zahra Shahsavari; Davood Omrani; Fatemeh Zeinali; Hossein Najmabadi; Theodora Katsila; Christina Vrettou; George P Patrinos; Joanne Traeger-Synodinos; Erik Splinter; Jeffrey M Beekman; Sima Kheradmand Kia; Gerard J Te Meerman; Hans Kristian Ploos van Amstel; Wouter de Laat Journal: Am J Hum Genet Date: 2017-08-24 Impact factor: 11.025