Genetic Testing 101…Sorting out Common Misconceptions
For this post we have a guest blogger, and I am very excited about this topic! If you have been in any EDS social media groups, you have probably noticed that every thread has different recommendations and explanations surrounding genetic testing. We cannot go through and correct all the misinformation out there, so I am hoping this post will help clear up some of the major disconnects. Because genetic testing is so nuanced, I reached out to a genetic counselor to walk us through the nitty-gritty of genetic testing, particularly in cases of EDS, which, as most of you know, is particularly complex.
As always, we love comments and feedback! What new things did you learn? Anything you still need clarification on? Let us know~
Alexa Barbagallo is a genetic counselor who graduated from Sarah Lawrence College. She was diagnosed with hypermobile Ehlers-Danlos after years of searching for answers. Alexa has a focus in pediatric and adult general genetics with a special interest in connective tissue disorders. She has conducted research into advocacy for rare diseases and maintains an interest in spreading awareness and support.
EDS and Genetic Testing
The Genetics of EDS
Everyone has two copies of every gene. One is inherited from their biological mother and one from their biological father. Most forms of EDS are passed down in what is called an autosomal dominant manner, which means that only one gene needs to have a change to cause symptoms; that gene was likely passed down from one parent (although it can be a spontaneous (de novo) change). Other EDS forms are autosomal recessive, meaning symptoms and disease only occur when both copies of a gene are altered, one copy from each parent. When someone is homozygous, that means that both copies of the gene have the same change. Someone with one changed gene and one standard gene is what’s called heterozygous.
Genetic testing is often considered the Gold Standard by which most variants of EDS are diagnosed. There are currently 13 known subtypes of EDS, and 12 of them have at least one gene known to be associated with that condition. The only exception is hypermobile Ehlers-Danlos (hEDS). hEDS does not have a confirmed gene; however, several genes of interest are being researched. Though the gene isn’t known, research does indicate that hEDS is passed down in an autosomal dominant way.
Genetic Testing
Genetic testing for EDS usually takes a panel approach. A gene panel only looks at a specific set of genes known to cause a particular condition or disorder. For EDS, a panel of genes known to cause connective tissue disorders is usually tested. Because panel testing does not look at all your genes, it cannot tell you general health information or about other possible genetic conditions. Panel testing is used most often since it’s the most targeted, cost-effective genetic testing option, and the one most likely to be covered by insurance. A commonly used panel, Invitae’s Connective Tissue Panel, covers 92 genes in total.
Whole genome testing looks at the entire genome, coding and non-coding bases, while whole exome sequencing looks at only the coding regions of the genome. These methods can give much broader results, though there is the risk of finding other results that may not be useful or wanted. These tests are more difficult to get insurance to cover, and they tend to take longer to get results; however, it is worth discussing with professionals if either is a good fit for you.
How is it Done
The specifics depend on the company or lab where the testing is done. Generally, a DNA sample is collected through either a blood draw or a cheek swab. The sample is then sent to a clinical diagnostics lab where DNA is extracted from the sample. If a panel is being run, then Polymerase Chain Reaction (PCR) is performed to amplify only the genes of interest. These PCR products are then sequenced. For whole genome sequencing, following extraction, the sample is fragmented into lengths that the sequencer can tolerate, typically around 150bp, and then the whole DNA library is sequenced. Finally, for whole exome sequencing, after the sample is extracted, it is fragmented, and then undergoes a protocol called target capture, where DNA probes, or small single strands of DNA that match the region of interest, can be used to pull out only the coding regions of the genome. This enriched library is then sequenced. A gene panel typically takes 3-4 weeks to return any results, whereas whole genome or whole exome may take longer, usually due to the more complicated analysis pipelines.
Most medical providers can order genetic tests; however, not all of them are trained to properly interpret the results. For proper interpretation and next steps, testing should be reviewed by an EDS specialist or genetics professional. Genetic counselors are professionals whose job is to interpret results in the context of family history to break them down in a way that makes sense, as well as provide additional support and resources.
Direct-to-consumer testing is frequently advertised for genetic testing. While this is an option for primary information gathering, it should not be used to make medical decisions, and frequently is not accepted by medical professionals for diagnosis or referral purposes. Regardless of where you get testing, it is very important to follow up with a professional regarding results as genetic information is incredibly nuanced and knowledge is constantly changing.
Possible Results
There are a few possible test results that can be of interest.
Positive Result: This is when the testing did find a detrimental change in a gene that is known to be associated with a type of EDS. This means there is a change in genetic makeup, and that change has been validated as a pathogenic change that will affect collagen formation in the body. The need for one mutated copy of a gene vs both copies mutated to be considered a positive result depends on the inheritance pattern, whether it is a dominant or recessive gene. Remember that in EDS, some forms are dominant, and some recessive. If the gene is recessive, one change, even if pathogenic and in a gene known to cause disease, is not a positive result. One change in a recessive condition signals that you are a carrier, which is good to know when considering having children. The result is only diagnostic when symptoms are also present in an individual.
Negative Result: This is when no change was found that is known to be associated with EDS. Usually, the changes in our genes are completely normal; it’s what makes us each unique. Genetic testing looks specifically for changes in our genes that have been proven to cause symptoms and impact health. With a negative result, all gene variations found are considered normal and would not explain symptoms. This does not negate any symptoms that you may experience; it could be that we don’t know the gene connection yet, as is the case with hEDS.
Uncertain Significance: These are commonly referred to as a Variant of Uncertain Significance” or “VUS”. Again, differences in genes between people are very common. Occasionally, labs see a change in a gene they know can cause disease, but can’t determine if the change is normal between people or possibly linked to the condition. A VUS result is like a “wait and see”; it means science hasn’t caught up yet to properly interpret the variant. VUS variants are constantly being reevaluated in light of new cases, so your genetic provider should keep you up to date on any new information. This also does not negate your experience or symptoms; it just means there isn’t enough data to be certain.
Some tests may also return with “limitations”; these are results in genes that were included on the test but are not generally well understood. Meaning that labs aren’t certain if that gene is associated or what variations might cause symptoms. Generally, these are treated as negative results until more information is found.
I’m positive, what does that mean?
Positive testing gives your medical providers an idea of what to look out for and how to manage symptoms. Certain EDS subtypes have different needs for referrals and follow-ups. You should discuss with your doctor what follow-up needs to be done.
Keep in mind that the results do not predict symptoms. Receiving a positive test result doesn’t mean you will experience every aspect of that condition. Different people with the same diagnosis have different lived experiences. Very similar to how one person with the flu may have a sore throat while another person has a very runny nose, no one's experience is the same, even in people with the same genetic change. Some people with a known change may not even develop symptoms at all, a concept known as reduced penetrance.
I have a negative or VUS result, but living with symptoms
Negative genetic testing does not mean there’s nothing going on. You should still continue symptom management with your doctors. If you had a gene panel done, perhaps a broader strategy such as whole genome or exome testing may return a result. A VUS result is very similar. You need to take care of yourself with your doctors, even if there is no genetic explanation right now. The field of genetics is constantly finding new genes, new variations, and new techniques. What is a VUS or limitation today could be better explained in the future.
Further Interest in Results
As I’ve stated, there are many variations in every single gene in an individual. These changes can be normal variability or perhaps associated with a condition. If you do go through genetic testing, you would receive the information of which gene is impacted, as well as a string of letters and numbers indicating the exact change noted. There are websites accessible to the public, namely ClinVar, where scientists pool known information about variants. These include notes about how often the variation has been seen, and sometimes what that person’s experience and symptoms were. ClinVar is still a growing database, so information is being updated constantly.
Sites mentioned:
https://www.invitae.com/us/providers/test-catalog/test-434340
