Date: Nov 02, 2016 Source: Science Translational Medicine (
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Authors:
Chandni V. Jain1,2,*, Leena Kadam1,2,*, Marie van Dijk3, Hamid-Reza Kohan-Ghadr1, Brian A. Kilburn1, Craig Hartman4, Vicki Mazzorana4, Allerdien Visser3, Michael Hertz1, Alan D. Bolnick1, Rani Fritz1, D. Randall Armant1,5,6 and Sascha Drewlo1,†
1Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
2Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
3Department of Clinical Chemistry, VU University Medical Center, Amsterdam, Netherlands.
4Safe and Sound for Women, 3131 La Canada Street, Las Vegas, NV 89169, USA.
5Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
6Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
↵†Corresponding author. Email: sdrewlo@med.wayne.edu
↵* These authors contributed equally to this work.
Science Translational Medicine 02 Nov 2016:
Vol. 8, Issue 363, pp. 363re4
DOI: 10.1126/scitranslmed.aah4661
Single-gene mutations are responsible for a large number of diseases and contribute to a sizeable fraction of pediatric hospitalizations and deaths. Current methods for prenatal diagnosis of such mutations are limited because they are invasive (except for detection of circulating fetal DNA, which is safe but can be difficult to perform accurately) and most cannot be performed early in pregnancy. Jain et al. now demonstrate a way to isolate and analyze trophoblast cells, which carry fetal DNA, by noninvasively obtained Papanicolaou smears. The authors show that analysis of the DNA in these cells presents an accurate reflection of the fetal genotype as early as 5 weeks of gestation, without the risk posed by invasive procedures.
Abstract
Single-gene mutations account for more than 6000 diseases, 10% of all pediatric hospital admissions, and 20% of infant deaths. Down syndrome and other aneuploidies occur in more than 0.2% of births worldwide and are on the rise because of advanced reproductive age. Birth defects of genetic origin can be diagnosed in utero after invasive extraction of fetal tissues. Noninvasive testing with circulating cell-free fetal DNA is limited by a low fetal DNA fraction. Both modalities are unavailable until the end of the first trimester. We have isolated intact trophoblast cells from Papanicolaou smears collected noninvasively at 5 to 19 weeks of gestation for next-generation sequencing of fetal DNA. Consecutive matched maternal, placental, and fetal samples (n = 20) were profiled by multiplex targeted DNA sequencing of 59 short tandem repeat and 94 single-nucleotide variant sites across all 24 chromosomes. The data revealed fetal DNA fractions of 85 to 99.9%, with 100% correct fetal haplotyping. This noninvasive platform has the potential to provide comprehensive fetal genomic profiling as early as 5 weeks of gestation.
Copyright © 2016, American Association for the Advancement of Science
