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.