Chapter 2, Part 4: prenatal diagnostic testing can lead to toxic knowledge

This is the fourth installment of Chapter Two’s dive into prenatal genetic testing. Previous installments are available here. This is the final section concerning prenatal diagnostic testing. Next week begins the sections on prenatal genetic screening.

As the Baylor Laboratory glossy exhibit flier demonstrated, as it was unfolded and condition and after condition was listed, advances had been made beyond the karyotype. Prenatal diagnostic testing was no longer limited to just looking at the physical chromosomes to see if there was an extra, or missing, or translocated chromosome. Now, laboratories can conduct chromosomal microarray (“CMA”) testing from an amnio or CVS sample. At another medical conference, a geneticist provided a helpful analogy.

Picture a set of encyclopedias. Each volume represents a chromosome, so that you have 46 volumes (or 47 in the case of a condition like Down syndrome, or even 45 in the case of a condition like Turner syndrome, AKA “monosomy X”). This is what a karyotype reports: how many volumes are there; are they in the correct order; is one missing?

What CMA allows is for the lab to open each volume and see each page, which is akin to seeing each gene on a chromosome. But the level of examination does not end there. CMA can read the actual words and even the precise letters on each page. CMA can report out whether there are pages missing from a volume or volumes, conditions called “microdeletions” like DiGeorge syndrome, also referred to as “22q” as it is a deletion from the 22^nd chromosome. But, CMA can also report out even more miniscule changes, deletions, and what are termed “variants of unknown significance,” or “VOUS’s.”

In 2013, ACOG, along with the Society for Maternal-Fetal Medicine (SMFM), issued a committee opinion to account for the advances made with CMA. In the case of known or suspected genetic conditions, ACOG recommended that instead of doing the conventional karyotype test for diagnostic testing, CMA should be used. Further, it recommended that when an amnio or CVS was being performed, it should be the option of the mother if she would like to have CMA performed.

ACOG made its recommendation with all the attendant caveats and recognitions: that due to the volume of genetic information that can be reported, the decision to have CMA should be an informed decision by the mother after pre-test counseling and with genetic counseling for interpreting the results being available. Chapter 5 will address the aspirational versus actual ability to fulfill these recommendations for informed decision. But for now, it should be noted that ACOG issued its position statement in the face of a published report that found some women described CMA as providing “toxic” knowledge.

The study was done of expectant mothers who had underwent CMA testing and their experiences with the results. Overwhelmingly, the women were surprised at the sheer amount of information reported by a CMA. In and of itself, volume of information is not necessarily reason for concern. But, what was contained in that volume of information was concerning to many.

CMA would get down to such a granular genetic basis that it would report out consanguinity—that the mother and father were related. It would report out information that was relevant to the mother’s health. For instance, where the CMA was performed due to suspicion of one genetic condition, it would show that that condition was not present, but that the female fetus had the BRCA1 or BRCA 2 gene—genes inherited from the mother which are associated with an elevated risk for breast and ovarian cancer. Meaning, not only did the female fetus have this elevated risk, but so, too did the mother.

Lastly, the VOUS’s would become a great source of anxiety. Contrary to the reassurance most of these women were seeking by initially accepting prenatal testing, they had been told their pregnancy was at an increased risk for some genetic condition, risked a miscarriage to have an amnio or CVS performed, told the CMA ruled out the suspected genetic condition, but that their child had some genetic condition variant that, frankly, the lab and their doctor was not sure whether it would negatively effect the child or not. Seeking reassurance, they received the exact opposite, hence the description of the information relayed by CMA as being “toxic.”

This lack of reassurance and reporting of unexpected results, with unexpected consequences, also is found in the next section on prenatal genetic screening.