One of the earliest genetic tests we had was simply looking at DNA under a microscope. By doing so, we noticed that most humans had 46 chromosomes (packages of DNA) of various sizes. These chromosomes come in pairs; one from Mom and the other from Dad. By studying them we learned that an extra or missing chromosome could cause huge health effects. We also noticed that smaller pieces of chromosomes are sometimes missing or duplicated. Those changes sometimes affect people’s health, and other times appear to have no effect at all.

Advances in genetic testing have allowed us to zoom in closer and closer on those chromosomes to find smaller and smaller changes. Nowadays, one of the most commonly used genetic tests is called a Chromosomal Microarray or CMA. As opposed to sequencing, which looks for letter changes within the genetic code, CMAs look for extra or missing pieces of DNA across the genome. We call these types of changes Copy Number Variants or CNVs. So, what does it mean if a CNV is found? Well that’s the tricky part.

Dosage Matters, Except for When it Doesn’t

The genes in your body are instructions to make proteins. Having an extra or missing copy of a gene affects how much or how little of that protein your body ends up making. For a lot of those proteins, having a little more or less than normal isn’t a big deal. For others, the amount of protein is very important; too much or too little throws the whole system off. Imagine you were making chocolate chip cookies and you accidentally added an extra half-cup of chocolate chips. You probably wouldn’t panic, right? You can tolerate a few extra chocolate chips per cookie (you might even prefer it). Now, imagine that instead you accidentally added an extra half-cup of salt. That would make a drastic change to the taste of your cookies. The effects these changes ultimately have don’t just depend on the dosage, but on the type of ingredients involved as well.

CNV Classifications

No one has a “master list” of all the possible CNVs and what they mean. There are roughly 20,000 genes in the human genome, and a CNV can involve any number of those genes. If you do the math on that, that gives you a lot of possibilities (probably infinity, but I’m not a mathematician). Because there’s so much variability involved, genetic laboratories have to put a lot of effort into interpreting these types of test results.

Most labs use a standard set of guidelines to try and determine what effect a particular CNV may have on an individual. If they determine there’s enough evidence to show that the CNV has negative health effects, they call it pathogenic. A benign CNV is one that has enough evidence to show that it does NOT have any health effects. Anything that doesn’t fall neatly into one of those two categories is called a CNV of uncertain significance. These types of CNVs are the most frustrating, because we’re left without a clear answer as to whether the CNV is important or not. If this type of CNV is found, testing of family members may be recommended to see if other people in the family carry the same change. Those studies might help clarify the results, but often we have to wait for more research to be done before a determination can be made. 

It Gets Complicated

Even when we have a found a pathogenic CNV, we can’t necessarily predict exactly how it will present itself in that particular individual. For example, one of the most common genetic conditions is called 22q11 Deletion Syndrome, sometimes known as DiGeorge Syndrome. It’s caused by a small deletion on chromosome 22, and can cause multiple conditions including heart defects, cleft lip, and learning disabilities. About 90% of people with this syndrome have a de novo change, or a new change not found in their parents. The other 10% of the time, one of the parents have the change too. Sometimes that parent is completely unaware that they had this change in the first place. They have such mild symptoms that they were never diagnosed. Why did the same CNV hardly impact the parent while having a severe effect in their child? We’re not sure. There may be other genetic or environmental factors that come in to play that we just don’t understand yet. The human body is complicated!

Chromosomal Microarrays are now some of the most commonly ordered genetic tests. If you or a loved one has this test, it’s important to keep in mind how complicated the results can be. Even CNVs that are known to have health effects can vary greatly in severity between individuals. As with any genetic testing, it’s important that your health care providers interpret the results in the context of the whole clinical picture.