Here, Genie, Genie, Genie...
Updated: Jan 18
When the Genetic Test Results for Confirming Charcot Marie Tooth Disease Generate More Questions Than Answers
The genetics of Charcot Marie Tooth Disease are complex and moving so fast that it’s difficult for anybody to keep up. The interpretations and explanations of genetic test results are often confusing and conflict with the text of the report. These reports don’t use the simple “Positive” or “Negative” terms. Instead, they use confusing terms and phrases that are then interpreted by the physician or clinician to mean something tangible and understandable for the patient population. What happens though, when the text of the genetic test results report doesn’t match what the physician explained as they determined that it’s not CMT, although symptoms strongly suggest a clear case of CMT? Charcot Marie Tooth Disease, being genetic, means that you are either born with it and have it, and will develop symptoms at some point, even if they never get worse than dismissively mild, or, you were not born with a gene mutation that causes CMT, and, therefore, do not and will not have CMT. When you’re symptomatic and everything points to CMT, but your genetic test comes back with either nothing, or Variants of Unknown Significance, where does that leave you? The answer might surprise you. Join me for a little story.
The Journey is Confusing
Whatever your journey, whatever the process, your physician has reason to believe you have CMT. You’re symptomatic. Your physician orders a Nerve Conduction Velocity (NCV) test. The results indicate findings that are consistent with an axon-related type of CMT. You are the first person in your family suspected of having CMT. Your physician diagnoses you with a probable Type 2 CMT, based on symptoms and on NCV findings. To be certain, your physician orders a genetic test that will confirm the diagnosis. After a few weeks, the results are in. Your physician calls you and says that the genetic test showed that you, in fact, and to everybody’s surprise, do not have CMT. Say, huh? Hold up. How can this be? Everybody was so certain. The symptoms match. The electrodiagnostics match. Literally, everything points to CMT. CMT answers all of your questions. You’ve learned so much from the CMT social media community while impatiently awaiting your test results. You’ve read even more online. Was all of this in vain? It doesn’t make sense that the genetic test proves you don’t have CMT. Your physician, looking right at the report, told you that you don’t have CMT. The physician is certain. It’s not even a maybe. It’s an absolute. You go in to see your physician a week later, for follow up. Your physician gives you a copy of the report, after discussing the report with you, and explains how it shows that you do not have CMT. Your physician, however, doesn’t explain the full picture captured in the lab report. Sound familiar? Your genetic test report suggests that you have a heterozygous Variant of Unknown (or uncertain, depending on author) Significance (VUS) identified in the FIG4 gene. The report goes on to explain that there is a known homozygous variant that is understood to cause a recessive type of Charcot Marie Tooth Disease. The report also states that the significance of the identified heterozygous variant in the FIG4 gene is unknown. Your physician interpreted the report to suggest that you do not have CMT. The internet disagrees, and further suggests that you have a variant that is associated with CMT4J. FIG4 is Where it’s At CMT4J is understood to be caused by a compound heterozygous variant in FIG4. CMT4J is also a demyelinating subtype. Remembering that your NCV results indicated nerve conduction characteristics that are consistent with an axon-related type of CMT, and you have a variant in a gene that is associated with CMT4J when there is a variant present, you are now more confused than ever, and none of this makes sense. I mean, you clearly have CMT, but your physician says that your test shows you don’t. How can this be? You ask your physician to clarify the results, and they insist you do not have CMT. They are still just as certain about the results. Does this still sound familiar? This fictional scenario is a far too common reality for many CMTers. Many CMTers are the first in their family to hear the words, “Charcot Marie Tooth,” in a description of what they are battling. There is no established family history of CMT. All of this is brand new, and the diagnostic journey is long and arduous. When there is a generation or two, or more, of genetically confirmed CMT in a family, a clinical presentation is far easier to diagnose. Physicians can order the genetic test for the exact gene mutation that’s already established in the family, and move forward. However, when there is a first-in-the-family presentation of CMT, obtaining the genetic confirmation can be exceedingly difficult. Let’s take a deeper look at our fictional genetic test from earlier.
The Results are In, or Are They? In short, our fictional test result suggests only that there is a mutation (variant) in a gene, that, when there is a completely different mutation present in that same gene, CMT is caused. In our example, there is a heterozygous variant in the FIG4 gene. This means that only one copy— called an allele, of the two copies of FIG4 have the identified mutation. Remember that our test result stated that a homozygous mutation in the FIG4 gene was associated with causing a recessive type of CMT? Well, the secrets reside in the terms used. But, they’re really not a secret. CMT4J is understood to be caused by a recessive (homozygous) mutation in the FIG4 gene. But, it’s not any random mutation that shows up in the gene. Specifically, the c.122T<C (p.141T) variant in the FIG4 gene is understood to cause CMT4J. And, because it’s a homozygous (recessive) mutation, both copies of the gene— both alleles, must have this same mutation to cause this subtype of CMT. The need for the specific mutation to be present in this gene in order to cause CMT4J can be further explained by comparing other disease-causing mutations in the FIG4 gene. A specific homozygous mutation in FIG4 causes CMT4J. A completely different homozygous mutation is understood to cause Polymicrogyria. Yet, an altogether different heterozygous (dominant) mutation in this same gene, different from the heterozygous VUS in our fictional test, is understood to cause ALS11. Additionally, there are variants of unknown significance in the gene. Only one variant in FIG4, a homozygous one, is understood to cause CMT though. Currently, there are no other mutations in FIG4 that are understood to cause CMT, in the published literature. There are linkages to CMT of other homozygous and heterozygous FIG4 variants. However, currently, these are not understood to cause CMT. Rather, these variants are only suspected to cause CMT. Additionally, other identified variants in FIG4 that were once suspected to cause CMT have been ruled out by researchers. For these reasons, and others, I’m careful with my description of understood to cause CMT vs. linkage to CMT. It’s Not About the Gene, But It's All in the Genes The gene does not cause CMT. An exact mutation in a gene is what causes the specific subtype of CMT. It’s not just any random mutation in a gene, and it’s not that the particular gene is mutated, and therefore causes CMT. That would be far too easy. With CMT, nothing is easy. With CMT, and especially the genetics of CMT, there is only complexity. The phrase, “a gene that is associated with CMT,” or the phrase, “a VUS in a gene that is associated with CMT,” or the phrase “a VUS associated with CMT,” etc., are misnomers. Genes are associated with CMT, sure; but genes are so associated with CMT by proxy only. The specific mutations in a gene are what are associated with CMT. And, it is these specific mutations that cause specific subtypes of CMT. The genes themselves do not cause CMT. As demonstrated by other mutations in the FIG4 gene, a gene that, when possessing a certain mutation that is understood to cause CMT, can have other mutations in it, and not cause CMT. This is how we know that it’s the mutation, and not the gene that causes CMT. It’s also how we know that it’s not just any mutation in a gene, but that’s it’s a specific mutation that causes CMT. Our fictional test suggested that there was a VUS. Variants of unknown significance are interesting for me, and they are also common. Many of the variants of unknown significance that are identified in genetic tests for CMT could very well end up becoming to be understood as causing yet to be named CMT subtypes. I have often read that a VUS means nothing with a CMT genetics test. CMTers have been told this by physicians and clinicians when discussing their test results. Saying that a VUS means nothing is a misrepresentation though. They just simply mean that what they indicate is not yet understood. What does all of this mean for our fictional test though, now that we have a solid understanding of what the terminology in the report represents? Our fictional CMT genetic test suggests that the results are not consistent with what one would typically expect to see for what would be considered to be consistent with a genetic confirmation for CMT. Basically, our fictional test results are negative for CMT. Our fictional physician was correct in interpreting the results to unequivocally prove that there is no CMT, right? Or, were they? What if I told you that there’s a lot of information missing from not just our test results, but from the narrative, too? This is where everything gets turned upside down, and where everything gets interesting.
Clarifying the Negative
Having a negative genetic test result is frustrating. However, it does not mean that CMT has been ruled out. It only means that the genes that were examined were not found to have the mutations that are understood to cause a named subtype of CMT when they are present in the genes that were tested. There are more than 100 gene mutations currently understood to cause CMT. There’s not any one lab that tests for all of them. Lab A’s full Complete CMT Panel, or whatever name the lab gives the test, might test 53 genes that are known to have mutations that cause CMT. Lab B’s Complete CMT Panel might test 43 genes that are known to have mutations that cause CMT. Yet, Lab C might test 60 genes. Neither of these labs will test for mutations in the same genes as the other. There isn’t a standard that labs have to adhere to when deciding what to test for as they design their panels. There are so many variables in the results for CMT genetic test results, especially when the report essentially results a negative for confirmation. It is my experience that physicians and clinicians could do a better job of explaining these variables, rather than simply accepting that it’s a negative result. Some physicians and clinicians may not know that their lab’s Complete CMT Panel tests only for 53 mutations that are known to cause CMT. They may not know this because the labs do a poor job of communicating these things. In Closing A negative CMT genetic confirmation test result does not necessarily mean that a person does not have CMT. There isn’t any one lab testing for all known mutations in any one test. Also, not every subtype of CMT has an identified mutation associated with it. A negative result literally only means that the specific mutations tested for were not identified as being present. And, the test result means literally nothing more than that. As with everything CMT, even a simple hypothetical about a genetic test turns into a complex discussion. However, understanding the terminology of genetic test reports and understanding the variables of the results helps to tear down some of the complexity, and it helps us to have informed conversations with our healthcare providers, with your loved ones, and with fellow CMTers. I’m not a physician or a clinician. If you are experiencing anything that is outlined in this article, it’s not my intent to determine if you do or do not have CMT. I’m not qualified to, and I would never attempt to give you any medical advice. If you are experiencing anything outlined in this article, I invite you to have a conversation with your healthcare provider about what we discussed here. Forward this article to them ahead of time if you feel it could help you with recall. Having that conversation after reading this article might help you and your care team to determine what is the best way forward for you. The genetic test results can be confusing and they can be intimidating. They don’t have to be though. I hope that, by this article, I was able to ease any confusion, I hope I was able to remove any intimidation held by test reports, and I hope I was able to provide insight into what a VUS on your report might indicate when the physicians and clinicians are silent on explanations about the VUS being the only findings in your test.