by Katie Stoll
Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetics.
At the recent National Society of Genetic Counselors Annual Education Conference in New Orleans, a presentation raised some important questions about noninvasive prenatal screening (NIPS). According to the speaker, a woman with a vanishing twin pregnancy underwent NIPS with an expanded microdeletion panel and the results showed findings “suggestive” of a chromosomal microdeletion syndrome.
The patient underwent amniocentesis with a SNP microarray and the results were normal. In a follow-up call with the NIPS lab, the genetic counselor learned that multiple copy number variants were observed (not originally reported) in the original sample. The lab suggested that these variants could be associated with a malignancy or fibroid tumor (and were of course unlikely to be associated with a microdeletion syndrome in the fetus).
As a result of this genetic counselor’s follow-up phone call and due diligence, the patient underwent an extensive work up for possible cancer, but no explanation was found. NIPS was repeated and this follow-up study was normal.
My first thought in hearing this case was – That poor woman! First a lost twin pregnancy, then concern for a severe condition in her baby, anxiety about the amnio, and worry that she may have Cancer. Although I am not a health economist, my second thought was – Holy Cow! How can our healthcare system afford all of the follow-up testing that may come downstream from these tests? NIPS is promoted as a test that will lessen the need for follow-up procedures such as amniocentesis, but will that remain true as the list of screened conditions increases?
In October 2013 Sequenom expanded their NIPS test to include screening for microdeletion syndromes and Natera followed suit in Spring 2014. Some new companies entering the NIPS market are also advertising screening for microdeletion syndromes.
The addition of microdeletions is a brilliant business strategy for expanding the testing market to include all pregnant women. Even though microdeletions are rare, their incidence—unlike that of Down syndrome –is not linked to maternal age. Women who are currently not offered NIPS because they are not included in the high-risk categories proposed by the American College of Obstetricians and Gynecologists (ACOG) guidelines could now be given a reason to undergo NIPS—even though the predictive ability of the NIPS for rare conditions is less than impressive.
Women who elect the test because of an interest in Down syndrome or because they are eager to learn fetal gender may unknowingly be screened for rare microdeletion syndromes which they know little to nothing about. To add to the complexity, a maternal microdeletion condition may be an incidental finding. In a poster presented at the NSGC meeting this year, Sequenom presented a series of 22q11 deletions detected with their MaterniT21 PLUS test. Included in this report were two mothers who were themselves incidentally diagnosed with 22q11 deletion syndrome. Based on the consent form on the Sequenom website it seems unlikely that these women had any idea such a result may occur.
Where is the evidence to support this expanded screening?
These tests are being performed despite there being no published clinical validation studies. There have been some case reports and proof of concept studies; however given that this testing has been commercially available for over a year now, there is shockingly little published about cell free DNA screening for microdeletions. An abstract from a poster presentation at the ACOG annual meeting in April 2014 evaluated 6 samples (or is it 7? – it is not clear from the abstract) from pregnancies known to be affected with microdeletions and 8 simulated samples. They conclude, “This is the most comprehensive, accurate validation of noninvasive microdeletion detection hitherto… This approach will enable accurate, noninvasive, prenatal population screening for these severe disorders.”
Proof of concept is one thing; proof of clinical validity is another. If we value evidence-based medicine, a sample of six (or seven) affected pregnancies is a long way from being a basis for population screening. Whether population-wide screening for extremely rare disorders is worth paying for is, of course, a question in itself.
But in the unregulated environment of laboratory-developed tests, we adopt first and report out results later. Accompanying this process is a lack of transparency – labs performing NIPS with microdeletions have not made performance statistics publicly available and thus patients and providers have no way of determining the accuracy of microdeletion NIPS. In a webinar hosted by Sequenom , the presenters were asked about the positive predictive value (PPV) of Sequenom’s screen for microdeletions. One speaker replied, “We have calculated them. However, what we would like is essentially to wait a little bit to give you more clinically relevant results. Because so much depends on the fetal fraction of the sample and so on and so forth, so we feel that the more appropriate number to release is after we have done 50,000 samples, how many have we found, how many have we reported back, how many were confirmed, how many were in line with the clinical picture.”
Shouldn’t the accuracy of the test be publicly known before it is run clinically on 50,000 women?
Labs have given us only a glimpse of their performance statistics. I was previously provided information from Natera regarding estimated PPVs for the microdeletions on their panel, but I cannot locate this information anywhere in the public forum. The table I was provided stated a 1/19 PPV (5.3%) for 22q11 with a Fetal Fraction >6% and dropping much lower (to 1/45) with decreased fetal fraction (interesting thread here of multiple women with a 1/19 chance of 22q11 on their NIPS result).
In a letter to the editor, former CMO of Sequenom Allan Bombard and colleagues reported that they had evaluated 264 samples from pregnancies with known microdeletion and microduplications or “enriched genomic mixtures” and report a 100% sensitivity and 99.3% specificity. Applying these statistics to 22q11.2 deletion syndrome (the most common microdeletion syndrome on the panel with an incidence of 1 in 4,000) indicates a PPV of about 0.036 or 3.6% . The overall PPV would be expected to be lower given the very low incidence of the other microdeletions on the panel. At the NSGC meeting this year, Sequenom presented some preliminary data from a series of 120,726 samples screened from October 2013 – July 2014 with test performance that exceeds those estimates. Although they did not have complete follow-up data for positive and negative results, a press release from the company following the NSGC meeting reports “high positive predictive values (estimated combined PPV ranged from 62% to 94%)”.
The limited information available suggests PPVs for microdeletion syndromes fall within a broad range of <3% – >90%. Published peer-reviewed studies are needed to help clarify the PPV associated with this testing so that healthcare providers and patients can make informed decisions about utilizing and interpreting this testing.
About a year and a half ago I published a piece on the DNA Exchange that discussed the importance of PPV in interpreting NIPS results. This was written for an audience of genetic counselors, but the posting is being increasingly used as a venue for patients to share their stories and seek information about their test results. Many patients report considerable anxiety – “the waiting is killing us…we have been devastated for the better part of 3 weeks now” – and some express regret for undergoing this testing at all, “I too wish I would of just done the typical old fashion test so nothing was in the back of my mind and hours of my life would be given back…” Recently, a woman remarked that she did not consent to additional testing for microdeletions and indicates her frustration with not being able to find information about the PPV for this test, “Not only are they essentially experimenting on us…they are not transparent about the potential problems with validity or low PPV.”
As genetic counselors, we are implicated in these companies’ approach. We should be demanding better evidence before leading our patients towards testing that could create this kind of distress. We need to be asking good questions, and we should demand good answers. If we cannot figure out how reliable a screening test is from a thorough review of the literature, I think we really need to ask ourselves if we should be offering it in a clinical setting.
The DNA Exchange 
I have, thus far, been fortunate that no microdeletions have been reported out on the tests ordered by my MFM group. In addition to the fact that it is difficult to consent patients for this portion of NIPS tests due to lack of published data, another concern came to light for me last week regarding insurance. A patient, who underwent MaterniT21 Plus testing in April, recently received a denial from insurance. The denial was based on the test being “investigative,” which was confusing to me, as the company (our local Blue Cross) has a medical policy outlining the typical high risk indications for coverage and this woman’s first pregnancy was affected with trisomy 18. After our appeal was unsuccessful, I ended up exchanging emails and phone calls with one of the medical directors. Ultimately, he cited the fact that the medical policy is for trisomies 21, 18 and 13 and nothing else. He is aware that there are additional conditions being screened on some NIPS tests and it seems that this was the grounds for the test denial. I believe I was able to persuade him to cover the test for this particular patient, given the very clear reason she was having the test performed (and the fact that the cost and billing code is the same with or without microdeletions). I think it is important for us all to know that some insurance companies are aware of the fact that there is not published data for the additional conditions screened with some NIPS tests and this may affect what tests are covered. I’m sure that, as GCs, we spend the most time thinking about these aspects of testing and I’m always concerned about OB offices who are routinely offering these tests to low risk women in place of first trimester or quad screens…
Thank you for your very thoughtful post. I agree with you wholeheartedly that if we cannot get better data from these laboratories, we should seriously consider whether offering these tests is in the best interest of our patients.
I received a referral for a NIPT positive for Angelman syndrome. I was shocked to learn from the laboratory that the PPV they quote for this result is 4%. The patient was also shocked that this test was even being offered with that low a PPV. She was not a “high-risk” patient to start with, and had not been fully informed regarding the NIPT and what was being tested for. It was a complicated counseling session, and ultimately the couple declined diagnostic testing and stated they would “try not to worry about it” for the rest of the pregnancy. Obviously this is easier said than done!
Our MFMs have elected not to order the microdeletion syndromes when ordering NIPT except in special circumstances. Pre-test counseling is key as you so eloquently address.
Thank you Katie for a really great post! Our large MFM/GC group is also opting out of NIPT microdeletion panels at this time (and we point to the lack of data supporting this testing in our clinical notes). A few exceptions apply. For instance, if we have a patient with an increased NT or fetal CHD and she declines to start with diagnostic testing, we will offer an expanded NIPT panel (with testing limitations emphasized). While our group is not offering expanded NIPT to low risk patients, this is becoming the norm for many of our referring OB offices. We have seen numerous patients with false positive NIPT microdeletion results. Most of these patients have had no pre-test counseling. We find many OB offices are happy to order this expanded testing but are then unprepared to clean up the resulting messes.
We have multiple OBs offering NIPS with microdeletion screening without any counseling about the nature of these disorders, PPV and the lack of published data. All positives referred to us have been false positives after diagnostic testing and tragically, patients have terminated pregnancies without diagnostic testing despite extensive counseling. We have carefully chosen our NIPS lab and admire them for NOT offering microdeletion testing. We hope that they will hold their ground and not jump on the bandwagon and begin offering microdeletion testing. These “additions” to the testing menu only circle us back to what NIPS promised to avoid: low PPV and unnecessary procedures plus huge patient anxiety and confusion. I think SCA screening through NIPS has similar problems and now extensively counsel patients about the difference between gender determination and screening for SCA since they can be ordered separately.
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Really relevant article- I’m in Western Australia and so far we haven’t heard much about the microdeletion panels, although they are available for patients privately. Non of the NIPT are being offered through our public system so at the moment we’re only seeing patients after a high risk NIPT result has been confirmed with diagnostic testing. Given the extremely low PPV with mcirodeletion syndromes I’m not sure whether we’ll need to reassess this, but this article couldn’t have come at a better time.
Thank you so much for this article. I am not a geneticist, nor a statistician, but a mother going through the most terrifying experience of her life. I tested high risk for cri du chat with a 1:19 chance of having it according to panorama. Nobody is giving any straightforward answers as to what this means. Like many, I had no idea I was being screened for this (even though I asked the office exactly what they were testing). I have been going through the worst month of my life. I had to deal with this situation while studying for my medical boards. I am waiting for my cvs results and each day that passes, my nerves keep building. I have read many cases of this being false positives but you can’t help but feel like you will be the unlucky one. I will keep praying very hard!
Just wanted to share
I too am a mother in australia and have also had the same result as you 1:19 for cri du chat after having the panorama nipt and i too am a nervous wreck!! we are 15 weeks and have just completed an amnio and are impatiently awaiting our results of the microarray. RB6577 it would be great to get in contact to know how you went, i hope you got a good result 🙂
What were your results? I received a 1:19 panorama panel for Digeorge Syndrome. I’m a nervous wreck. I go in for my amnio on 2 weeks.
How were results? I’m a wreck trying to figure out if I’m the unlucky one. I received a 1:19 chance for Digeorge syndrome. Go in for my amnio in 2 weeks.
Hello. We just just had a positive result with Maternity21 for 15q deletion (Angelman/Prader-willi). We are shocked!!!
You mentioned having a referral for a NIPT positive for Angelman syndrome.Did the your patient’s baby end-up having the syndrome?
We are desperate and don’t know what to do:
-1 Repeat NIPT in different lab?
2- Go for CVS or Amnio?
3-wait..?
Thank you very much
Ezequiel – I encourage you to meet with a genetic counselor to talk through the possible next steps. You can find a directory of genetic counselors in your area at nsgc.org
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if you’re doing cfDNA research at academic institute, and biobank is precious to you especially those associated with clinical data, you don’t want 2-5 mL plasma for extraction of cfDNA because you could run out of your biobank very quick!! I found out that now CirculoGene Diagnostics can do droplet volumes of blood to recover cfDNA for cancer monitoring by NGS (2015 ASCO abstract)..its so cool!!.before only Theranos can do it in a drop of blood and mostly they do chemistry testing, not genetic test.
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