Jeffrey S. Buguliskis Ph.D. Technical Editor Genetic Engineering & Biotechnology News

New Approaches in Genomic Medicine Are Helping Future Parents Eliminate the Risk Of Common Inherited Genetic Abnormalities

As one of the more controversial topics in diagnostics today, reproductive genetic testing (RGT) has become a lightning rod for political rhetoric and a font of misconception within the general populace. Science fiction would have us believe that RGT will be used to make designer super babies that are disease free and have perfect features.

However, the current medical reality is seemingly more pragmatic by typically assisting couples with reproductive difficulties obtain genetic screening and counseling during in vitro fertilization (IVF) procedures, as well as help all future parents eliminate the risk of common inherited genetic abnormalities.

Traditional genetic screening techniques have relied on observation methods using either customary histology stains (G-banding stain) for gross chromosomal analysis or the use of specific fluorescent markers (FISH analysis) that hybridize within chromosomes that are common for aneuploidy—defined as an abnormal number of chromosomes within the cell. The advantage of these techniques is their speed, low cost, and validated methods for determining genetic abnormalities. However, to obtain the genetic material often requires the use of invasive techniques that carry some risk for the developing fetus.  

Rapid progress in genomic medicine over the past several years has allowed researchers to detect and diagnose discreet genetic abnormalities within a clinical setting. Prenatal genetic screening is a field where this is becoming a mainstay of clinical medicine. Women are routinely administered a variety of genetic screening tests within the first trimester in order to detect chromosomal aneuploidies, as well as other inherited abnormalities. Many of these tests come in the form of ultrasonograms or they use maternal serum markers, which typically suffer from high false positive rates.

Positive tests for fetal abnormalities will often lead to much more invasive methods like chorionic villus sampling (CVS) or amniocentesis. However, many women are uncomfortable with the idea of such invasive procedures, as they carry a 1-2% risk of inducing a miscarriage. However, many companies and institutions have been developing new screening methods that are more accurate and carry much less risk.

Genomics Helps NIPT Invasiveness in the Bud

“There is a clear need within the prenatal reproductive space to access genetic information from unbiased fetal material so that downstream testing can have the necessary diagnostic accuracy and clinical value,” explains Radha Duttagupta, Ph.D., senior scientist at Affymetrix. “These materials can include fetal cells or nucleic acids for non-invasive prenatal testing (NIPT) or cells from the early pre-implantation embryo.”

In the past several years with the rapid advances in next-generation sequencing (NGS) technology, prenatal testing has begun to shift focus toward less invasive techniques. NIPT offers clinicians and patients an extremely accurate intermediate step between serum-screening assays and invasive procedures such as CVS. As the economics surrounding NGS continues to drive the price of sequencing ever lower, many clinicians feel that NIPT will eventually replace current methods as the gold standard for embryonic testing.

“NGS is an example of a new technology that has both advanced the development of new genetic tests and improved existing ones,” states Bob Rochelle, vp of marketing at Good Start Genetics. “NGS is already having an impact on medicine: from reproductive testing such as carrier screening, NIPT, and preimplantation genetic screening to genome sequencing for refined diagnostics and tumor sequencing.”

NIPT involves analyzing cell-free fetal DNA (cffDNA) that is present and obtained from a maternal blood sample. This method is extremely useful for determining risks from aneuploidy diseases such as Downs syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13) or sex chromosome disorders like Turners syndrome. Additionally, these tests can be used to determine the sex of the fetus and rhesus blood type. 

Various sources of genetic material can be used by NIPT methods, such as RNA and even intact circulating fetal cells, but only cffDNA is abundant and stable enough to be the most appropriate for this form of genetic testing. Coupling the acquisition of fetal DNA with massively parallel sequencing techniques, allows test developers to create a faster and ultimately cheaper screening tool. Yet, with every new genomic advancement comes obstacles that need to be tackled to allow for wider acceptance within the clinical arena. 

“The challenge is determining how to translate that need into an actionable test,” notes Rochelle. “First by understanding the underlying biology and second by adapting the technology to focus on the right things in an accurate way that predicts a clinically meaningful outcome.”

Test validation is always a concern for the manufacture, as well as regulatory agencies that evaluate new methods for clinical efficacy. Proper validation addresses the diagnostic measurement techniques as well as the accuracy of the clinical results. 

“One of the biggest challenges in test development is accessing an adequate number of appropriate clinical samples to properly validate performance specifications of the test for its intended use,” points out Dr. Duttagupta.  “Prospective collections are typically expensive and time-consuming, and laboratories often rely on sample registries that may have coverage gaps or insufficient quality and quantity to be included in the studies. These limitations challenge both the ability to make clinical claims as well time to market because of increased development and validation timelines.”

If the accuracy of detection and rate of false positive is any indication of clinical validation, then many of the NIPT using cffDNA analysis coupled with NGS platform technology are even more precise than currently employed testing measures. A recent study in Fetal Diagnosis and Therapy selected all peer-reviewed articles on cffDNA testing in the screening for aneuploidies between 2011 and 2013. The authors found that the tests were 99% sensitive for trisomy 21 at 99.9% specificity, 97% sensitive for trisomy 18 at 99.9% specificity, and 92.1% sensitive for trisomy 13 at 99.8% specificity. This data shows NIPT are highly sensitive, with an extremely low false positive rate between 0.1–0.2%.

“The rapid adoption of new genomic tests such as NIPT by the healthcare community has resulted in unprecedented sample volumes. This has created a need for high-throughput processing and reduced assay turnaround time and cost while continuing to maintain a high level of assay performance,” says Dr. Duttagupta. “Hence, detection technologies that deliver rapid and reliable testing are powerful enablers of test development.” 

Various sources of genetic material can be used by NIPT methods, such as RNA and even intact circulating fetal cells. [iStock/HYWARDS]

Future of Reproductive Genetic Testing

Even a cursory glance of the current scientific literature and diagnostic test manufacturers marketing material would be enough to indicate that the field of RGT is funneling most of its efforts into noninvasive genomic-based screening techniques.

“Reproductive genetic testing will continue to advance in the amount of content that can be assessed using next-generation sequencing, and thus the amount of helpful information it can yield,” explains Rochelle.

As sequencing technologies continually improve, the number of genetic conditions that can be simultaneously detected through noninvasive methods will expand exponentially. This could conceivably create a new direct-to-consumer market for couples beginning the reproduction process or those who have already experienced difficulties in conceiving. 

“Based on the fact that couples are choosing to conceive progressively later in their lives, and that more information can be gathered around the reproductive choice, we are likely to see an uptake of all reproductive testing, spanning pre-gestational genetic screening (for carrier diseases), NIPT, and preimplantation genetic diagnosis/preimplantation genetic screening in the in vitro fertilization process,” adds Dr. Duttagupta.

Additionally, one of the major goals ahead for NIPT is to move to the sub-chromosomal level and focus in on copy number variation analysis with high reliability as many NGS platforms are currently doing for other genetic diseases, such as cancer. However, patient education and informed decision making will become a particularly difficult obstacle to overcome, as low genetic literacy and the absence of highly trained genetic specialists are already cause for concern. 

“High-volume NIPT will create a need for more comprehensive education and counseling where the clinically appropriate interpretation of test results and the need for follow-up confirmatory testing is clearly described to the patients,” says Dr. Duttagupta.

Invariably, high-tech advancements bring the need for better education to understand the output. Yet, in most cases progress brings along with it not only new ways to view the problem but diverse ways to simplify the learning process associated with high-tech improvements.

“The technological advances and growing knowledge in reproductive genetics will lead to significant advances in our ability to empower patients and increase access to tools that can improve health and/or pregnancy success rates,” explains Rochelle.  

This article was originally published in the November 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to

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