Prenatal Chromosomal Microarray (CMA)

To the Point- Prenatal chromosomal microarray (CMA) is a genetic testing methodology, performed on cells obtained through amniocentesis or CVS, that can detect tiny bits of extra or missing genetic information (known as copy number variants or CNVs) that are too small to be detected by traditional karyotyping techniques. CMA can also detect the conditions found by traditional karyotyping techniques (traditional karyotype is the test that gives you a picture of the chromosomes), for example, Down syndrome. Besides the possibility of detecting over 150 genetic conditions, there is a small chance that chromosomal microarray may detect what is termed, a variant of unknown significance (VUS).  A VUS is a change in the baby’s DNA that may or may not affect the baby’s development but there is not enough data to know for sure.  Chromosomal microarray may be offered to all women undergoing invasive testing, such as amniocentesis or CVS, but especially if your baby has an abnormal ultrasound finding or there is some other high-risk indication.  This test is optional and is always your choice. 

Results
How to Decide
FAQs

The Basics

Prenatal chromosomal microarray (CMA) is a genetic test that can be performed on cells from either the amniocentesis or CVS procedure.  CMA is a genetic testing methodology that can detect tiny bits of extra or missing genetic information (known as copy number variants or CNVs) that are too small to be detected by traditional karyotyping techniques. CMA can also detect the conditions found by traditional karyotyping techniques (traditional karyotype is the test that gives you a picture of the chromosomes).  Prenatal chromosomal microarray is a newer technology and is sometimes offered in addition to the traditional karyotype analysis because of an abnormal prenatal ultrasound finding or other reasons that may make the pregnancy high-risk.  However, with increasing frequency, this test is being offered as an option, in addition to or even instead of, the traditional karyotype analysis for any pregnancy undergoing amniocentesis or CVS.

In addition to being able to look for chromosome abnormalities involving a whole extra chromosome (trisomy), such as, Down syndrome, and abnormalities involving a missing chromosome, prenatal chromosomal microarray can look for additional genetic conditions.  Microarray testing has the capability to essentially zoom in on parts of the chromosomes that are too small to visualize using a microscope, allowing detection of smaller regions of extra or missing portions of the chromosome.  Conditions in which several genes or instructions are missing are called microdeletion syndromes. Conditions in which there are several genes duplicated are called microduplication syndromes. Microdeletion and microduplication syndromes are often associated with intellectual disability and birth defects. There are over 150 genetic conditions that can be detected with microarray testing.

Besides the possibility of detecting conditions such as Down syndrome and microdeletion and microduplication genetic conditions, microarray testing may also detect what are called variants of unknown significance (VUS).  These are changes in the baby’s DNA that may or may not affect the baby’s development but there is not enough data to know for sure. Recent studies have shown that approximately 1.4-2.1% of patients receive a result that is a VUS1.  Many labs request samples of mom and dad’s blood to look at their DNA to help interpret the meaning of a VUS; in some cases this can be helpful but not always.  When a VUS is found in the baby during the pregnancy, it may cause a lot of anxiety in mom and dad as the outcome for baby may be very uncertain.  This is one of the main reasons that genetic counseling and informed consent prior to having prenatal chromosomal microarray is very important.  Other things to keep in mind with chromosomal microarray include the following:

  • CMA does not identify all genetic diseases or birth defects
  • Diseases that are identified may vary from mild to severe in terms of outcome and it may not even be possible to predict outcome in some cases
  • CMA may reveal non-paternity (father of the baby may be different than was thought)
  • CMA may reveal that mom and dad are closely related (e.g. cousins)

Prenatal chromosomal microarray may be offered to all women undergoing invasive testing, such as amniocentesis or CVS, but this is an optional test and is always your choice.

How it Works

Prenatal chromosomal microarray (CMA) is performed on cells from CVS or amniocentesis.  How prenatal chromosomal microarray works gets a bit complicated.  So, taking a step back, we need to explain a bit more about what a microarray is….

mi·cro·ar·ray

noun: microarray; plural noun: microarrays

1. a grid of DNA segments of known sequence that is used to test and map DNA fragments.

An easy way to think about chromosomal microarray is that thousands and thousands of single stranded DNA (gene) sequences have been stuck on a tiny glass square on specific spots within a grid.  The people in the lab know what genes or DNA sequences are on each spot on the grid and can keep track of all of this.  By the way, the fact that the DNA on the microarray is single stranded is important – usually DNA is double stranded and it likes to be double stranded.  The cool part comes next.

When they receive your baby’s cells from the CVS or amniocentesis, the laboratory takes the genetic information (DNA) from inside those cells and turns it into single stranded DNA (again, it is usually double stranded and likes to be) and also breaks it into smaller pieces.  Along with your baby’s DNA the lab uses a control DNA and mixes the two and puts them both on the microarray and then the amazing occurs.

So, like we have been saying, single stranded DNA would rather be double stranded.  DNA is made up of bases, namely A, T, C, & G.  A pairs with T and C pairs with G, always.  So, if you have a sequence of DNA that is A-T-C-G, it is GOING TO FIND a DNA strand that is T-A-G-C and hook up, literally.

Your baby’s DNA fragments and the control DNA “search” the microarray until they find their match and then they “hook up”.  And, this is what leads us to the beauty of this technology.  We have explained above that this test can look for regions of the chromosome that have extra genes or missing genes.  If there are extra genes “hooking up”, the microarray test will show that more of the baby’s DNA hooked up (microduplication syndrome) to the microarray than the control and if there is a region of missing genes (microdeletion syndrome), the test will show that the baby’s genes did not “hook up” to the microarray.

The way that the test keeps track of baby vs. control DNA is by attaching a color to each.  Control is GREEN and baby is RED.  If equal amounts of control and baby hook up, the result is that the microarray looks yellow in that grid.  If it is green, it means that there is more control DNA and baby may be missing some genes in that region (microdeletion syndrome).  If it is red, it means that there is more baby DNA than control DNA present and there may be a microduplication syndrome present.

Prenatal chromosomal microarrays consist of hundreds or thousands of gene (DNA) sequences, which can be analyzed simultaneously.  This technology also allows for determination of whether or not all of the chromosomes are there or if there is any extra chromosomes as is the case with conditions like Down syndrome, just as traditional chromosome analysis and also whether or not you are having a boy or a girl!

Results

Amniocentesis or CVS with prenatal chromosomal microarray (CMA) is considered a diagnostic test and results are thought to be definitive (yes or no). However, no test is perfect and there are cases when the results are hard to interpret or rare cases of lab error.  With CMA, you will receive information on the chromosomes (looking for evidence of Down syndrome and other Trisomies), gender as well as whether or not any microdeletion or microduplication syndromes have been detected.  CMA does not rule out all genetic conditions or all birth defects, some types of CMA cannot detect a condition called triploidy (3 copies of all of the chromosomes), and it cannot  detect balanced chromosome rearrangements.  CMA also may detect non-paternity (father of the baby is not the same as was previously thought) and consanguinity (mom and dad are closely related to each other, for example, cousins).

My CMA results are abnormal….what should I consider?

If you are reading this and you have received an abnormal result, it may be that you are finding out that your baby has Down syndrome  or it may be something much more severe, such as Trisomy 13 or Trisomy 18 , or something potentially more mild, such as Turner syndrome (45, X) or Klinefelter syndrome (47,XXY) or it may be a microdeletion or microduplication syndrome. No matter what condition has been diagnosed, we know that this is not necessarily an easy time or what you expected.

If your results indicate a chromosome condition, genetic condition or birth defect, it is often very helpful to take time to talk to your provider, a genetic counselor if you are able, friends and family if you are comfortable, and even get a second opinion if you feel like that may be helpful. Taking time and consulting with others is especially important if your results are confusing, unclear, or if you don’t know much about the condition that has been diagnosed.

Even if you know a bit about the condition, it’s often helpful to get up-to-date information as things have changed dramatically for some conditions. For example, in the case of individuals with Down syndrome, quality of life and life expectancy is quite different than it was 2 generations ago. Also, depending on what website you go to, who you talk to, what you read, you are going to find differing opinions on what life may be like for a child with the condition that has been diagnosed, what it is like to parent a child with the condition, etc. Some people benefit from finding someone who has a child with the same diagnosis and speaking with them directly. Your provider or genetic counselor may be able to help facilitate this.

Ultimately, you have 3 options if you find out through amniocentesis that your baby has a chromosome abnormality, genetic condition or birth defect….

  1. Continue the pregnancy and prepare – READ MORE
  2. Continue and place the baby for adoption – READ MORE
  3. Choose to not continue the pregnancy – READ MORE

 

My CMA results indicate a variant of unknown significance (VUS), what should I consider?

First of all, you are not alone.  Studies vary, but approximately 1/50 individuals who undergo CMA receive a VUS result.  This is not easy. At all.

Before we go any further, we are making some basic assumptions at this point…

1)   You and your partner have had your blood drawn to look for the variant and this has been discussed with you (if not, this is your next step as if it is found in mom or dad, it may provide you with some reassurance if you are healthy)

2)   Your provider has searched the literature and has not been able to find enough evidence to tell you, with confidence, the outcome/prognosis for your baby

So, here you are…you have this information and you don’t know what to do with it, it may be causing you a fair amount of anxiety, and you may be stuck with more questions than you had before you started on this testing trail.  We unfortunately don’t have all of the answers for you either.  But, one thing that may be helpful is to see if your provider can connect you with another person who has been down this same path before you to give you support and comfort during this challenging time. We wish we could tell you more…with time hopefully we will be able to.

How to Decide

Part of deciding about having prenatal chromosomal microarray means first taking a step back and deciding about whether or not to have invasive testing, such as, CVS or amniocentesis.  For more information about amniocentesis, including information on how to decide about whether or not to have that procedure, click here.  For more information on CVS, click here. But, if you have already decided on having amniocentesis or CVS and are now trying to figure out if you should just have the traditional chromosome analysis (karyotype analysis) or the chromosomal microarray, keep on reading….

There are certain situations where microarray will be offered or recommended based on abnormalities on ultrasound, but keep in mind that this testing is always the patient’s choice.  In cases where the baby has been found to have an ultrasound abnormality, research has shown that the chromosomal microarray definitely improves the chances of finding out what is going on with the baby versus standard karyotype analysis alone; one study showed that in these cases 6% were found to have an abnormality detected by CMA when traditional chromosome analysis was normal…but, there are still aspects of this test that are worthwhile to consider as you will read below.  If you are being offered chromosomal microarray for no specific indication, below are some thoughts to consider.

Prenatal chromosomal microarray is an exciting technology that is relatively new within the arena of prenatal testing.  Before assuming that more is better, you may want to take a step back and think about a few things.  First of all, do you want to know all of this information in the first place, and would it change your decisions about how you would proceed with the pregnancy.  Secondly, and often understated, there is a real chance, 1/50 or greater, that you may get results that indicate there is a difference or change found in the baby’s DNA (called a variant of unknown significance or VUS), but we don’t know exactly what it means because technology is ahead of us.  The VUS may or may not cause problems in the baby and the prognosis may be uncertain.  This can cause a lot of anxiety.  Microarray testing during pregnancy cannot be equated with microarray testing after the baby is born, when you can actually see the baby, know what he/she looks like, etc.  Finding out uncertain information about the prognosis of the baby during the pregnancy can be especially challenging and make decision-making extremely difficult.  Microarray testing may also reveal information about the future health of the parents and also may detect things like non-paternity (if the father is someone other than previously thought) and consanguinity (if parents are closely related to each other).   Like other prenatal testing options, the choice is always up to you to make.

Patients often ask their doctors or genetic counselors, “would you have the amniocentesis or CVS with prenatal chromosomal microarray?” This is a great question, however, the answer is different for each individual and circumstance.   One of the most important aspects of prenatal genetic counseling is that whatever the patient decides is based on their personality, beliefs and values, not the providers.  So, instead we offer you some questions to consider.

  • Do you feel like you need yes or no answers to be able to enjoy the rest of the pregnancy, eat, sleep, etc?
  • Do you feel like you are ok waiting until the baby arrives to know for sure?
  • If you feel like you need more definitive answers, are you ok with the risk of miscarriage associated with these procedures (amniocentesis- <1/200, CVS, <1/200)?
  • If you knew that the baby had a chromosome abnormality such as Down syndrome, would it affect your decision to continue the pregnancy and raise the child?
  • Would you consider other options if there was an abnormality, such as, placement of the baby for adoption (which is a realistic option) or termination?
  • Have you thought about these two scenarios- 1) you don’t have the amnio/CVS and you find out at delivery that the baby has a chromosome abnormality and 2)you do have the amnio/CVS and you end up miscarrying the baby.  Both situations may be unsettling, but which scenario is more unsettling to you?  These are ethically challenging things to think about and talk about….this is part of why your provider will allow you to make these decisions based on your own personality, beliefs and values. 
  • Are there other trusted people in your life that you can turn to for advice and perspective (i.e. religious leader, family member, friend, etc.)?
  • Do you feel like you want to know all of the information from a chromosomal microarray or would you be ok with the information you can get from a traditional chromosome analysis?
  • Have you considered the chance of getting a result indicating a variant of unknown significance and how you may react to that?
  • Are you the type of person that likes to try newer technology (like CMA in the prenatal setting) or are you the type that likes to wait until technology has been around longer and more of the kinks have been worked out?

References

1.  Hillman et al. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet Gynecol 2013; 41: 610–620.