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Non-invasive prenatal test at five weeks of pregnancy?

The latest developments in prenatal technology may make it possible to test for genetic disorders one month into pregnancy.


The test was revealed in Science Translational Medicine1, journal of the American Association for the Advancement of Science. The non-invasive testing — Trophoblast Retrieval and Isolation from the Cervix (TRIC) — gives the same accuracy as the more invasive amniocentesis test, yet can be used five to 10 weeks earlier than current testing modalities.

TRIC was first publicized in 2014 in studies led by Randall Armant PhD, principal investigator and Professor of Obstetrics and Gynecology, Wayne State University School of Medicine; and, Sascha Drewlo PhD, co-principal investigator, Associate Professor of Obstetrics and Gynecology, Wayne State, who joined the team in 2014.


The new method isolates and retrieves several hundred fetal cells that migrate from the placenta into the uterus. Using a technique akin to the common Pap smear, this test can be done as early as five weeks into pregnancy.


Armant and Drewlo in a related paper published Sept. 23 in Nature: Scientific Reports 2"Altered Biomarkers in Trophoblast Cells Obtained Noninvasively Prior to Clinical Manifestation of Perinatal Disease" — describes the correlation between levels of fetal cell proteins isolated by TRIC in the first trimester with the development of intrauterine growth restriction. The test was created to predict preeclampsia in the last trimester, and/or kidney disorders in the mother, including identifying if there is a small, undernourished fetus in the womb.


"The finding suggests it might one day be possible to test protein levels and identify pregnancies at risk for complications. Such a test could help physicians better manage the health of mother and baby and streamline research of new interventions which prevent/limit the effects of disease."

Randall Armant PhD, Principal Investigator, Professor of Obstetrics and Gynecology, Wayne State University School of Medicine, USA.


The Science Translational Medicine 1 paper demonstrates the ability to isolate fetal DNA from cells obtained by TRIC. As the placenta is derived from embryo DNA, it is the same as that of the fetus, so researchers can use TRIC cells for prenatal genetic testing.

The sequencing was completed in 20 consecutive pregnancies collected at five to 19 weeks, with minimal maternal DNA contamination.

"We used next-generation sequencing and accurately determined the nucleotide sequence down to a single base. TRIC could be used as a noninvasive test, with the accuracy of invasive tests like amniocentesis, and the ability to perform the test five to 10 weeks earlier than current testing modalities," Drewlo added.

The research was initially supported by a two-year exploratory grant given to Armant and colleagues in 2012 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health to test capturing human fetal cells for genetic study. A paper on their investigative work from that time was published in the journal Fertility and Sterility in 2014.

"Because the cells we purify by TRIC are placental cells that have a critical function early in pregnancy, their protein profile has been examined to determine if it becomes different in pregnancies that have serious complications like a miscarriage, undersized fetus or preeclampsia," Armant explained.

Continuing their investigation of obstetrical complications, the team's next goal is to identify new biomarkersusing global screens, beyond those proteins already tested and identified.


"For fetal genetic studies, we next plan to determine if TRIC can identify genetic disorders in the fetus. This would give parents information about the likelihood of their fetus having a genetic disorder much earlier in pregnancy than current tests. Very soon, we would like to begin clinical trials with all of these potential tests."

Randall Armant PhD


Noninvasive peek at fetal DNA
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
1: Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal
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.


Abstract 2: Altered Biomarkers in Trophoblast Cells Obtained Noninvasively Prior to Clinical Manifestation of Perinatal Disease
A contributing factor to poor placental perfusion, leading to intrauterine growth restriction and preeclampsia, is the failure of invading extravillous trophoblast (EVT) cells to remodel the maternal uterine arteries during the first and second trimesters of pregnancy. Noninvasive assessment of EVT cells in ongoing pregnancies is possible beginning three weeks after conception, using trophoblast retrieval and isolation from the cervix (TRIC). Seven proteins were semi-quantified by immunofluorescence microscopy in EVT cells obtained between gestational weeks 6 and 20 from pregnancies with normal outcomes (N = 29) and those with intrauterine growth restriction or preeclampsia (N = 12). Significant differences were measured in expression of PAPPA, FLT1, ENG, AFP, PGF, and LGALS14, but not LGALS13 or the lineage marker KRT7. These findings provide for the first time direct evidence of pathology-associated protein dysregulation in EVT cells during early placentation. The TRIC platform provides a novel approach to acquire molecular signatures of EVT cells that can be correlated with pregnancy outcome.

The research was supported in part by the Intramural Research Program of the NICHD, NIH grants HD071408 and HL128628, the W.K. Kellogg Foundation, the March of Dimes Foundation and PerkinElmer Health Sciences Inc.

For more information on TRIC testing and the Center of Advanced Trophoblast Research, visit drewlolab.com. To learn about supporting their ongoing research efforts, call the WSU School of Medicine's Office of Development and Alumni Affairs at 313-577-5929.

About Wayne State University School of Medicine
Founded in 1868, the Wayne State University School of Medicine educates more than 1,000 medical students in all four classes. In addition to undergraduate medical education, the school offers master's degree, Ph.D. and M.D./Ph.D. programs in 14 areas of basic science to about 400 students annually. Wayne State University is a premier urban research institution offering more than 380 academic programs through 13 schools and colleges to more than 27,000 students.

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