Can chip technology detect genetic abnormalities in early pregnancy?

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Improved noninvasive testing to detect genetic abnormalities early in pregnancy has been a goal of researchers, and now a team of Australian and Russian biomedical engineers has developed a tiny microfluidic device that could pave the way for such testing. Known as lab-on-a-chip (LOC), the device can screen large volumes of blood and distinguish fetal cells from maternal white blood cells in a sample. The device is a variation on a similar chip that was developed to separate tumor cells from blood in patients with cancer.

Dr. Marnie Winter and Professor Benjamin Thierry of the University of South Australia and RC Centre of Excellence in Convergence Bio-Nano Science and Technology led the team, which published findings from a pilot study in Advanced Materials Technologies.

Invasive and noninvasive genetic testing

Currently, amniocentesis and chorionic villus sampling (CVS) are the gold standard for definitive prenatal testing. They can only be performed early in pregnancy (CVS is usually done between 12 and 14 weeks and amniocentesis between 15 and 18 weeks). They are typically offered to mothers older than 35 years or those who are otherwise at high risk of carrying a child with a chromosomal abnormality based on a first-trimester nuchal translucency ultrasound and measurement of the maternal serum analytes free beta hCG and PAPP-A. These first-trimester screenings are, however, confounded by a high false-positive rate, leading to potential over-screening with CVS and amniocentesis. 

Circulating free fetal DNA (cffDNA) was discovered in 1997, and several noninvasive prenatal testing (NIPT) technologies have been developed in an attempt to better screen for aneuploidy and other monogenic disorders. However, when used to detect common microdeletions, genome-wide screening, copy number variants, single-gene disorders, and X-linked disorders, these tests have lower positive predictive values than for aneuploidy, leading to more invasive testing than may be necessary. “These tests have revolutionized prenatal care,” Dr. Winter said in a university press release, “but they can only detect a small subset of genetic conditions and are not always accurate. We hope the LOC technology will be able to reliably detect a greater range of genetic abnormalities, providing more information to families and healthcare providers.”

LOC feasibility and pilot study results

It’s been known for over 100 years that beyond five weeks of pregnancy, fetal cells circulate in the maternal blood after being shed from the placenta, and the researchers suggested that the ability to isolate intact fetal cells would “undoubtedly vastly improve the performance of NIPT.” In a feasibility study, they were able to isolate a high yield (79%) of trophoblastic cells from maternal peripheral white blood cells using the LOC inertial microfluidic technology. They then validated that fetal cells could be used to diagnose aneuploidy in a confirmed case of fetal trisomy 21 in a pilot study, by enriching six circulating fetal cells from a single 7-mL blood sample. In a second feasibility study, they were able to show that the technology could pick up single fetal trophoblast, demonstrating that LOC was compatible with “downstream genetic analysis.”

Results of these initials tests must be validated in a clinical study, but represent a new avenue for noninvasive genetic testing during pregnancy. If validated, the LOC device could reduce the number of invasive genetic tests performed as well as provide reassurance for low-risk mothers, the authors said.