The American College of Medical Genetics & Genomics (ACMG) has issued a new statement on cell free DNA prenatal screening. As with its initial statement, the ACMG separates itself from existing statements and guidelines on cfDNA screening.
When Sequenom launched MaterniT21 in October 2011, it took some time for professional organizations to issue their statements on its recommended use. The American College of Obstetricians and Gynecologists (ACOG), with the Society for Maternal Fetal Medicine (SMFM), issued a joint statement in November 2012. The following Spring, ACMG issued its first statement, with the National Society for Genetic Counselors (NSGC) following with its own statement.
At that time, ACMG set itself apart most notably by giving cell free DNA screening a new name (noninvasive prenatal screening or “NIPS”), not limiting its offering to just high-risk moms (as ACOG/SMFM and NSGC did), and stating that patients should receive identified resources with a screen-positive result. In similar fashion with its latest statement, ACMG has set itself apart from the updated statements and practice bulletins issued by the other organizations.
What’s in a name?
In 2013, ACMG’s initial statement was one of the first to note what was actually being tested by the then-referred to NIPT or noninvasive prenatal testing. While early reports and marketing materials by laboratories claimed to be testing “fetal” DNA–to emphasize the testing’s accuracy–ACMG corrected these representations by noting it was DNA from the placenta that was being tested.
In the new statement, ACMG again notes what is being tested, but retains its previous acronym of NIPS. From the statement:
Advances in genomic technologies led to noninvasive prenatal screening that relies on the presence of cell-free DNA derived from the placenta but circulating in maternal blood, which is referred to here as noninvasive prenatal screening (NIPS).
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We emphasize that all genetic screening has residual risk (i.e., risk of having a genetic condition even after receiving a negative or “normal” result). … The concept of residual risk supports our use of the acronym NIPS, where “S” represents screening.
“NIPS,” while helpful by emphasizing that cell free DNA testing remains a screening, and not a diagnostic, test, never has caught on in the published literature. Perhaps it induces too much snickering. But, ACMG is sticking with it, while others have taken to referring to NIPT as “cell free DNA screening.”
To whom is NIPS to be offered?
Here, again, ACMG separates itself from the pack. Until ACMG’s statement, ACOG/SMFM’s practice bulletins were the most recent organizational statement on cell free DNA screening’s administration. While ACOG/SMFM lifted its prior restriction of cell free DNA screening to only high risk expectant mothers, the practice bulletins made the point that for low risk patients, conventional screening remained the most appropriate screening. ACMG does not share ACOG’s view on what is appropriate screening for low risk patients.
Instead, ACMG recognizes cell free DNA screening as an appropriate screen for all expectant mothers. It bases its recommendation on studies that show even among the general population of patients, cell free DNA screening provides more accurate information, with lower false positives, than even the most accurate conventional screening (e.g. stepwise sequential screening) with results available earlier than conventional screening.
For what conditions is NIPS recognized?
ACOG/SMFM’s practice bulletins recognize cell free DNA as being clinically valid for a finite number of conditions: Trisomy 21, 18, 13, and for detecting the sex of the child. Laboratories offering the testing, however, advertise that their screening tests will detect many more conditions. Contra ACOG/SMFM, ACMG recognizes cell free DNA screening for many more conditions, but with several requirements for offering screening for these other conditions.
Regarding the sex chromosomes, ACMG recommends that providers deter patients from selecting screening for sex chromosome aneuploidy (SCA) for the sole purpose of detecting the child’s sex. But, ACMG recognizes cell free DNA screening for SCA, provided patients are advised of the higher chance of false positives for those conditions.
ACMG further recognizes cell free DNA screening as valid for copy number variant (CNV) conditions, such as 22q11.2 deletion, though ACMG acknowledges there are few clinical utility studies concerning cell free DNA screening’s performance for CNVs. ACMG makes the point that it is not recommending cell free DNA screening for genome-wide CNVs (though some laboratories are offering such testing).
What is to be provided patients with a screen result?
On this final section, ACMG’s statement provides more specific recommendations than other existing statements. One of the conditions for recognizing cell free DNA screening for conditions beyond Trisomy 21, 18, and 13, is that laboratories offering screening for SCAs and/or CNVs are to also provide “easily recognizable and highly visible” detection rates, specificity, and positive and negative predictive value with a screen result.
ACMG is also keen on pointing out that with the growing amount of information cell free DNA screening can report, both pre-test counseling and post-test counseling are needed, with post-counseling, specifically, to be provided by a trained genetics professional.
Lastly, for each screen-positive result for each of the conditions tested-for (e.g. Trisomies 21, 18, and 13, SCAs, and CNVs), patients are to receive “accurate, balanced, up-to-date information and materials at an appropriate literacy level when a fetus is diagnosed.” (emphasis in original). As with its 2013 statement, ACMG further identifies patient resources but also adds provider resources for delivering a diagnosis and healthcare guidelines for the tested-for conditions.
As before, ACMG separates itself from other organizations’ recommendations regarding cell free DNA screening. Unlike ACOG/SMFM and NSGC, ACMG recognizes cell free DNA screening as an appropriate first-tier prenatal screen for all expectant mothers for a wider array of conditions than any other organization recognizes. At the same time, ACMG requires of the laboratories more specific information about the accuracy of test results and requires of providers that patient support resources be provided.