Chromosomal microarray (CMA) is a technology that the American College of Obstetricians and Gynecologists now recommends be offered as a first-tier test for any woman undergoing diagnostic testing to replace the standard karyotype that has been used in practice for prenatal diagnosis for decades. This is a big change in practice; while the result may be an increase in the number of genetic differences that can be diagnosed through prenatal testing, it also comes with more uncertainty for expectant parents and healthcare providers who are trying to make sense of the results that may come from this testing.


First let me give some background on why the CMA test is different than the karyotype using the analogy of a library.  The nucleus of each of our cells contains our genetic information.  Imagine the nucleus to be like the library of the cell.  Each of us have about 20,000 pairs of genes, and each of these genes could be considered to be like an individual instruction book that tells the body how to build a specific protein that will have a specific job in our body.  The proteins that are built from our genes do everything that our bodies need to grown and function.  Our genes, (aka instruction books) are organized on chromosomes.  In this analogy, consider each chromosome to be like a large bookcase.  


The karyotype is a picture of the chromosomes and basically allows us to look at and count these bookcases.  In doing this we can see if there are any extra or missing bookcases (chromosomes).  Typically humans have 23 chromosomes inherited from their mother and 23 from their father in matched pairs, so 46 all together.  An extra or missing chromosome causes specific genetic conditions.  For instance, a baby with Down syndrome has inherited an extra copy of the 21st chromosome.    


The karyotype can also allow us to see if there are big structural changes in the chromosomes.  You could imagine this to be a scenario in which a few book shelves had been completely removed from the bookcase (so now a 10 shelf bookcase is a 7 shelf bookcase, for example).  This type of big change can be seen in looking at a picture of the chromosomes.  


The chromosomal microarray (CMA) test is different in that it allows us to see smaller genetic changes than can be seen by looking at the karyotype.  These changes are often referred to as Copy Number Variants, or CNVs.  A CNV is a segment of genomic information that has been duplicated or deleted.  So think of this as the equivalent of a few books on a shelf that have been removed (a deletion) or there are multiple copies of the same few books on the shelf (a duplication).  


Sometimes CNVs are known to cause genetic conditions resulting in health and developmental concerns.  Sometimes we are unsure what will result with certain CNVs.  Other times we see CNVs that appear to be completely normal variations, in which case we do not think they will cause any health or developmental concerns.  


With the karyotype, we usually have a pretty good idea of generally what to expect when we find  an extra or missing chromosome, or when there is a large change in the structure of a chromosome.  


But with CNVs, the meaning of the results is often much less clear.  Sometimes a CNV will be reported as being of “uncertain significance” which means that we just don’t know enough about it yet to determine if it is likely to cause health and/or developmental concerns or not.  Sometimes we find a CNV that we think will cause a health problem, but exactly what that will be or how severe it will be is unknown.  Sometimes when there is uncertainty, it will be recommended to test the parents to see if ether of them also have the same CNV.  This may provide some reassurance if a parent has the same CNV and they are in good health.  But we know there can be differences in how these variants are expressed from parent to child.  Furthermore, there can be situations in which a parent learns they also have the variant identified in the baby or their child, and rather than providing reassurance it leads to more questions.  Is there something wrong with me?  Did I pass on something harmful to my baby?  


Formerly, the American College of Obstetricians and Gynecologists recommended chromosomal microarray be considered  as a prenatal testing option in instances where there were abnormalities seen on ultrasound.  This is because in about 6% of those cases, CMA would provide an explanation that karyotype could not.  In other words, there would be a CNV (a few extra or missing books on a shelf) that karyotype could not see that could provide an explanation for the ultrasound findings.  


Research has found that in cases where ultrasound and karyotype are normal, a significant CNV that is believed to be likely associated with some health or developmental effect will be seen in 1.7% of cases.  Considering this, ACOG now recommends that CMA be made available to ALL women considering diagnostic testing such as amniocentesis.  


This means that more babies will be diagnosed with genetic conditions that would not have been identified from the traditional karyotype test.  It also means that many more families will be receiving information about their babies that may be unclear.  As genetic tests become increasingly complex, it is of utmost importance that women and couples receive pretest genetic counseling so that they can really understand all of the potential benefits, drawbacks, and uncertainties inherent with these tests.  

New Practice Guidelines for Prenatal Genetic Testing

Important guidelines in the area of prenatal genetics were recently published in the journal, Obstetrics and Gynecology (aka “The Green Journal”).  The American College of Obstetricians and Gynecologists (ACOG) and the Society of Maternal-Fetal Medicine (SMFM) collaborated on two new important references:  Practice Bulletin #162 Prenatal Diagnostic Testing for Genetic Disorders, and Practice Bulletin #163 Screening for Fetal Aneuploidy.  These are the first updated guidelines on these topics in nearly a decade and each offers a thorough assessment on currently available prenatal testing technologies as well important points to consider for any provider who provides prenatal care.  They are companion pieces and we encourage you to read them in their entirety when you have an opportunity. Below we summarize the highlights.  
Practice Bulletin number 162:  Prenatal Diagnostic Testing for Genetic Disorders

In 2007 ACOG shook things up by stating that all women (not just those deemed to have a higher chance to have a baby with a genetic condition) should have the option to undergo prenatal diagnostic genetic testing.  This recommendation did not change with the updated guidelines.  ACOG/SMFM still contend that all women should have the option of prenatal testing, including diagnostic tests such as amniocentesis and chorionic villus sampling (CVS). What has changed are the number of prenatal testing options.  With a growing number of testing choices, the decisions faced by expectant patients and couples are more complex than ever before. From the guideline:  


It is important that patients understand the benefits and limitations of all prenatal screening and diagnostic testing, including the conditions for which tests are available and the conditions that will not be detected by testing.”  


This is a great expectation!  Certainly even providers who think about these tests day in and day out struggle in deciphering the different benefits and limitations of each of these tests, as well as the variable conditions that each test may detect!  While it is perhaps a lofty goal, Genetic Support Foundation agrees wholeheartedly with the importance of this statement above. It is essential that individuals be provided enough information and context to make informed decisions when it comes to prenatal genetic testing.

Key updates with guideline #162:

  • Chromosomal microarray analysis should be the primary offered diagnostic method when ultrasound indicates structural abnormalities in the fetus.  Microarray should be made available to any patient choosing to undergo invasive diagnostic testing.  
  • New research indicates that the risk for miscarriage associated with amniocentesis and chorionic villus sampling may be lower than previously reported.  In the hands of experienced providers, the guideline suggests a miscarriage risk of 0.1% – 0.3%.  

Practice Bulletin number 163:  Screening for Fetal Aneuploidy

This document provides an excellent overview and nice comparison table of the various prenatal screening tests available for the assessment of chromosome conditions in the fetus. Technologies reviewed in detail include serum screening such as the triple and quad screening, combined screening such as first trimester screening, integrated screening and sequential screening and the more recently available cell-free DNA screening. The most important take away is that choices about prenatal screening options are complex.  


No one screening test is superior to other screening tests in all test characteristics. Each test has relative advantages and disadvantages. Screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision making that fits the patient’s clinical circumstances, values, interests, and goals.”  


Key points with guideline #163:

  • Women who have any negative screening test should not be offered subsequent screening tests. Parallel testing with multiple screening tests should not be done.
  • Cell-free DNA screening is not a replacement for diagnostic testing.  
  • Any woman with a positive screening test including traditional serum screening or cell-free DNA screening results should be offered follow-up genetic counseling and the option to undergo diagnostic testing.
  • Women who undergo preimplantation genetic diagnosis should be offered aneuploidy screening and diagnostic testing.
  • Cell-free DNA screening for microdeletions is not recommended.  
  • Cell-free DNA screening is not recommended for multiple pregnancies.  

In the future, we will explore some points raised in these two guidelines in more detail including, the potential for toxic knowledge with chromosomal microarray testing and why genetic counseling in these situations. We will also explore the potential issues with predicting a lower risk of miscarriage associated with diagnostic testing at a time when some studies suggest that the risk may actually increase as fewer women undergo these tests and providers become less practiced in performing the procedures.  

One point that we strongly agree with is this:  

“Screening for aneuploidy should be an informed patient choice, with an underlying foundation of shared decision making that fits the patient’s clinical circumstances, values, interests, and goals.”  

Whether you are are patient, a healthcare professional, or policy maker, we at the Genetic Support Foundation hope that you will find information here on our website that will help support this goal.