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ACMG Cautious of Non-invasive Prenatal Diagnostic Testing in Policy Statement

NEW YORK (GenomeWeb News) – While non-invasive prenatal diagnostic testing methodologies may offer advantages over traditional invasive methods, they also have limitations, and tests such as amniocentesis and chorionic villus sampling "should remain an option for patients seeking a definitive diagnosis," the American College of Medical Genetics and Genomics said in a policy statement issued last week.

In the statement, which was published in Genetics in Medicine, ACMG said that the use of NIPDs "has arrived," but outlined a set of wide-ranging concerns about the technology.

"The isolation of fetal DNA fragments from maternal circulation in sufficient quantity and sizes, together with proprietary bioinformatics tools, now allows patients the option of noninvasive fetal aneuploidy screening," ACMG said. "However, obstetric care providers must become familiar with the advantages and disadvantages of the utilization of this approach as analysis of cell-free fetal DNA moves into clinical practice."

ACMG's statement comes as a number of NIPD makers have jumped into the fast-growing market. Sequenom launched the first such product, the MaterniT21 Plus test, in the fall of 2011 and estimates that the high-risk market segment for NIPD testing, including trisomies 21, 18, and 13, to be approximately 750,000 patients per year just in the US.

In 2012 the San Diego-based company had a run rate of about 120,000 tests for MaterniT21, and for 2013 it guided to a run-rate of between 150,000 and 200,000 tests.

Since Sequenom launched its test, Natera, Ariosa Diagnostics, and Verinata Health, now part of Illumina, have launched their own NIPDs.

Additionally, in the fall the American College of Obstetricians and Gynecologists issued a favorable opinion for NIPD methods, and a growing list of national payors have been throwing their support behind the technology.

But even as adoption of such tests grows, ACMG said that they are not always appropriate. In addition, it noted that although studies have demonstrated high sensitivity and specificity with low false-positive rates for NIPDs, specificity and sensitivity "are not uniform across all chromosomes," and false-positive screening results do occur on occasion.

"For women seeking a definitive diagnosis, invasive procedures for diagnostic testing, such as amniocentesis or chorionic villus sampling, should be offered," ACMG said.

The association mentions 10 limitations of NIPD technology. They include results that are limited for the most part to T21, 18, and 13, though some tests, including Verinata's and Natera's, also test for certain sex chromosome abnormalities.

ACMG also said that NIPDs will not detect certain chromosomal abnormalities, such as unbalanced translocations, deletions, and duplications; they cannot distinguish specific forms of aneuploidy; and they do not screen for single-gene mutations.

The technology can also result in "uninformative" results, which can delay a diagnosis "or eliminate the availability of information for risk assessment," said ACMG. They also take longer for results to be returned than tests results on maternal serum analytes, and they don't screen for open neural tube defects, according to the association.

Additionally, NIPDs do not replace the utility of a first-trimester ultrasound examination, and there is limited data on their use in twins and high-order pregnancies, said ACMG. NIPDs also don't have a role in predicting late-pregnancy complications.

In its statement ACMG suggests that genetic counselors, prenatal care providers, and trained designees advise patients about the tests before their administration. Areas that should be discussed with patients include an explanation of what an NIPD is used for; the advantages of the method, compared to maternal serum analyte screening; possible follow-up testing using invasive techniques if NIPD testing indicates an increased risk for aneuploidy; and the limitations of NIPD testing.

ACMG also emphasizes that NIPD is not a diagnostic test but rather a screening method, and the association seeks to rename such products "screenings" rather than tests to indicate that they predict risk rather than provide definitive results, as The Wall Street Journal reported last week.

Lastly, ACMG wants the test makers to "make serious efforts" to provide positive and negative predictive values, which it says are "the more clinically relevant metrics."

"This could be accomplished through a funded registry at which efforts are made to confirm and archive not only true positives, but also false positives and true negatives," ACMG said.

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