Intro
Genetics is a newer, not fully understood field. Actually, this is something we can say of quite a few of our medical specialties. Many patients and providers are unaware of how much we do not know about the human body. Remember how lobotomies and blood letting were more commonly used in medical practice? Or how we were told that glial cells were just cushioning, or filler, in the brain and served no functional purpose? Well, now we realize that things like glial cells will be the key to figuring out how to help those with a variety of neurological conditions. It’s a neuroimmune cell, coordinating communication between the two systems. The early message was wrong, and now we are learning from previous misconceptions.
This is important to know how far off the mark we’ve been before. It’s important to understand that we don’t know everything right now, so we can’t say that variants of unknown significance that pop up in our genetics do not cause problems. There’s not enough research to support or deny these claims. The “unknown” significance means they don’t know. Similar to the word “idiopathic” in diagnostic terminology – it doesn’t mean there isn’t a cause of the problem at hand; we just don’t know it. I think we’ve made this particular point clear in our connective tissue world. Where is that hEDS gene?
I am not a geneticist; I do not give out diagnoses. But I work with individuals in deciphering the story of their genetic components. I guess you could call me a functional gene analyst. I look at the polygenic story someone’s genetic code creates, to see how the individual may work to reduce these particular risk factors. I’ll paint a picture here with some of the things we are finding within these genetic stories.
Connective Tissue Issues
Connective tissue disorders are disorders of the extracellular matrix (ECM). I talk about this on various YouTube videos, in my books, and ad nauseum in the clinic. Depending on someone’s particular genetic makeup they may have a structural or functional issue with their extracellular matrix. Some people have both. Structural issue examples would be with a variety of collagen. Functional issues would be with enzymes or other components within the body that can break down the extracellular matrix.
If you’ve heard me talk before (or some of our other keen providers), you have heard that hypermobility is a sign of a connective tissue disorder. For many, it’s not the main health issue. Feel free to drop into that YouTube video where I chatter on about the extracellular matrix and it’s response to inflammation here: https://youtu.be/zU0oskY2Ah4?si=BjmseOVXnpiX3Puy
This ECM dysfunction is a very important concept to understand, and it separates providers that are specialists in hypermobility versus connective tissue disorders.
Within my clinic, I have seen many individuals pop up with col1a1, col4 varieties, and col11 as well. Sometimes these are intron variants (see below in “My doctor told me the testing is inadequate.”). Less common are other col varieties like col6 and col9, along with some of those functional markers like TNXB or TGFBR1. I have rarely seen the kallikrein gene pop up, and have yet to see a KLK15, but I know they are out there.
Even if these variants of unknown significance pop up, the most we can say as providers is: “we don’t know what this means.” Just because it’s currently not supported in the research doesn’t mean that it also won’t be ten years from now. So, in my office, I think it is more important to educate someone on where in the body the gene activity is located and what that gene is programmed to do. (Also to note- we don’t know what all of our tissue is made up of precisely throughout the body and at what ingredient ratios. This will probably take a few more decades once our providers and researchers realize how important connective tissue is for overall health stability. There is more in that YouTube video listed above.)
There’s a trending post I’ve seen going around about the new organ: the interstitium. It’s not new, we’ve just finally started looking into scientific theories presented in the mid 1900’s by researchers looking into the extracellular matrix (thanks Dr. Psichinger!).[1] The interstitium is a type of extracellular matrix just like barrier systems and connective tissue proper like tendons, ligaments, and bone. For now, I visualize it in those three categories: the functional interstitial organ, the barrier systems, and the connective tissue proper throughout the body.
The interstitium is where most of our cellular communication and function happens. This is where cytokines travel through, mast cells exist, and even the landing point of our autonomic nerve endings. If this becomes overridden with inflammation, it can create strain on this interstitium. For those with a dysfunction in the structure or function of the extracellular matrix, pathology can develop. This will alter the cellular activity in the interstitium and can create a self perpetuating cycle of dysfunction.
Emerging research shows us that stiffness between these layers is a problem for those with connective tissue issues.[2-4] Interstitial stiffness is related to the presence of chronic disease.[5, 6] The interstitium should be malleable and dynamic, constantly shifting the internal environment depending on the body’s needs. If the inflammatory loads become too much, the interstitium cannot keep up and stasis, or stiffness, will occur. Genetic alterations may increase the risk, or predispose an individual, to developing issues like this. This happens between other tissues in the body as well and is most likely the cause for a good deal of neurological phenotypes and presentation of multiple vascular compressions.
Genetic variations that affect the structure or function of the extracellular matrix may predispose an individual to a more difficult time regulating inflammation in these spaces. Add in additional genetic predispositions (polygenic presentations) and now we may see where connective tissue disorders may look “progressive” in nature.
Inflammation Control Issues
Not only can we have issues with the interstitial space itself, or barriers and other forms of connective tissue, an individual can have difficulty regulating the inflammatory response within this space. This problem would be related to genetics linked to mast cell or autoimmune presentations. This does include hereditary angioedema, or anything within the complementary pathways as well (and other genetics of course). There are many genes to look at within this category.
If someone has difficulty initiating the appropriate response to a “threat” in the body, a fire hose of cytokine activity could be unleashed in this interstitium rather than a trickle. In someone with altered structural or functional control of the physical space of the matrix, this now becomes more of an issue to try and rebalance the system.
Knowing which genes are involved may help us be more precise with treatment. I’d like to say that working on everyone’s reason for inflammatory triggers is helpful (I love a good connective tissue detox!), but there are some individuals that have become dysregulated to the point that they do need precise immune specific medication to stabilize this first, before we go in an manipulate detox pathways or try and move things through the system. I have seen autoimmune related treatments to be much more successful with precision in knowing a possible main culprit genetically, what that gene is doing (or not doing), and then targeting that specific pathway. Is it Yao syndrome, Lupus, or C1 inhibitor deficiency?
And no, autoimmune flare ups don’t just happen because it’s a Tuesday. There is always a driver, or a trigger that can be addressed but the timing of all of this has to be right. Timing and specificity is where functional medicine related strategies can become tricky and easily go wrong without deeper understanding of these layers.
Neurological Reactivity Issues
I snuggle this in here as I have many patients dealing with more significant dysautonomia or the neurological phenotype of hEDS. Genetic variation information within the neurological categories can give us insight into how an individual’s neurological tissue may respond when irritated. Different genetic variations may make an individual more prone to neurological inflammation and hyper excitability, or neural degenerative changes. There are also some genetic markers for conditions such as familial dysautonomia and sensory and autonomic peripheral neuropathy that can be reviewed with sequencing. Variants in genetics don’t always mean that there is a firm diagnosis label that can be given, but predispositions toward similar presentations may be more possible.
There are techniques for clearing out and stabilizing the connective tissue slowly over time. I find the testing results alone can be very validating for the symptoms a patient is experiencing and help the patient have some footing under them to begin different treatment strategies. For our alternative medicine practitioners, it may encourage closer attention to deeper treatments into neural irritants such as viral, mold, or tickborne pathogens.
Bonus Plumbing Problems
Connective tissue issues can create difficulty dealing with inflammation in certain tissue spaces. Autoimmune or inflammatory related variants may increase the risk factor for having excessive or inappropriate inflammation responses to something considered a threat when the alarms are activated. Both issues can create a backup in the interstitial spaces and irritate other tissue layers. Eventually, this can shut down the lymphatic pumps when they become overwhelmed and create stasis or stiffness in these spaces.[6, 7] Genetic abnormalities in detox pathways can also reduce the body’s ability to clear out these spaces. And yes, there are genes that code different aspects of the detox pathways.
The detox pathways need to be working efficiently to drain the connective tissue and keep it clear of these pathogens and toxins. More often than you think, individuals may have a gene deletion in their GSTT1 (20% or more of the population) and/or GSTM1 (possibly up to 50% of the population), which will significantly affect the way toxins are removed from the body.[8] There are a variety of other genes that can be tested as well. These individuals will typically require some adjunct way to help detox their system occasionally throughout their lifetime. This may include but is not limited to red light therapy, oxidative therapies, lymphatic drainage manual work, Epsom salt baths, sauna treatments.
Should I Get Full Genome Testing?
I don’t know! Not everyone wants to know everything in their genetics. Not everyone is ok knowing that they carry the APOE gene that increases the risk for early onset Alzheimer’s or the BRCA1 gene that is related to breast cancer. Having a full genome sequenced commercially and released directly to the consumer will allow access to everything. Just because a gene pops up does not mean you have the label that is used in the diagnosis column. That’s what we have our geneticists for. If you want a diagnosis, you must see a geneticist. Until then, it is just interesting information.
Hopefully one day, people will be empowered by all the information in their genetics to know how to make positive changes and reduce the risk of those “scary” genes that may cause issues in the future. It’s thinking in the realm of health and wellness, rather than illness. There is a lot we may be able to do, improve current health, and prevent future health conditions with this information.
Even if I have patients that have this done, I do highly recommend that they follow up with a provider as soon as possible to sit down, review genetics, and answer any questions one may have.
My Doctor Told Me the Testing is Inadequate.
That depends on the test. There are some companies that go through the same certification process that the testing our geneticists are using. Make sure that the company is certified if you are looking to have this done commercially.
Also to note, for those that have been told that the information on commercial testing is wrong because nothing came up on the testing that was done with the company the geneticist used – well this can happen for two reasons. One issue is that the particular test most commonly used to look at connective tissue disorders only tests exons on the gene, which is where 80% of human disease is found. Well…we haven’t found hEDS yet, so what about looking somewhere else? Introns are not always tested on some panels! And yes, newer research is showing that intron variations can cause significant presentations in an individual.[9-12] The other reason is that it can depend on how one is searching a full genome, if a full genome sequencing with introns and exons has been done. If using AI generated reports, only the ones confirmed in the scientific literature will be provided to the patient or provider. To search for ones not listed in AI generated reports, one would have to access the database and type in each gene they may be curious about. Remember, collagen type 4 is not currently listed under a connective tissue disorder (collagen!!!). A provider may not know they have to look elsewhere within the testing platform. It will depend on the genetic company used.
Who Do I See For All of This?
I don’t know and I’m sorry to say that. The EDS specialists I typically work with in genetics continue to run exon only panels. When full genomes are done by some specialists, individual genetics are not always investigated, relying on reports with scientific backing only, or variations are brushed off if they are found to be of “unknown significance.” For all we know, the majority of the “unknown” category label may have a name to it in ten years. It currently does not mean “nothing.” We truly just don’t know. But if you understand that variations may affect the efficiency of what that particular gene is supposed to do, we can paint the picture like the short story we started to tell through this blog.
Outside of the genetic world, we still have specialists that hyperfocus in their field and those in functional medicine that do tend to favor one pathogen over another. It’s not that simple when it comes to connective tissue, especially when the interstitium is involved. It’s inflammation in general, and we’ve been exposed to just about everything as humans – polluted air, smog, household VOCs, mold, plastics, chemicals in food, viruses, etc. The provider must understand how all of these systems and gene variations may interact with each other. And also – how do we stabilize the individual in the long term? Medications for symptom relief or focusing on only one issue will not do this (although I’m all for appropriate symptomatic relief!).
Personally, I’m hoping as more research is released on the extracellular matrix role in inflammation and connective tissue disorders, the information will spread, and it will become commonplace. Unfortunately, it typically takes a decade or more for scientific information to become more common knowledge in clinical practice. As we are guided by the lens of research, this leaves it up to the treating providers to continue to connect the dots in order moving the proverbial needle.
Post-Script Sidebar: This blog post does not include specific information about genetic deletions. It is something I am currently digging into understanding and will likely be the topic of a future blog.
References:
- Pischinger, A. (2007). The extracellular matrix and ground regulation: Basis for a holistic biological medicine. North Atlantic Books.
- Wang TJ, Stecco A. (2021). Fascial thickness and stiffness in hypermobile Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet, 187(4):446-452. doi: 10.1002/ajmg.c.31948. Epub 2021 Nov 6. PMID: 34741592.
- Wang TJ, Stecco A, Schleip R, Stecco C, Pirri C. (2023). Change in gliding properties of the iliotibial tract in hypermobile Ehlers-Danlos Syndrome. J Ultrasound, 26(4):809-813. doi: 10.1007/s40477-023-00775-7. Epub 2023 Feb 19. PMID: 36802027; PMCID: PMC10632250.
- Wang, T. J., Schubart, J. R., Wagner, W., Mills, S., Joyce, R. L., & Francomano, C. A. (2025). Intersection between hypermobile Ehlers-Danlos syndrome and adipose disorders: investigating fascial remodeling with ultrasound imaging. Journal of Rare Diseases, 4(1), 52.
- Pfisterer, K., Shaw, L. E., Symmank, D., & Weninger, W. (2021). The extracellular matrix in skin inflammation and infection. Frontiers in cell and developmental biology, 9, 682414.
- Engin, A.B., Nikitovic, D., Neagu, M. et al. (2017). Mechanistic understanding of nanoparticles’ interactions with extracellular matrix: the cell and immune system. Part Fibre Toxicol , 14, 22. https://doi.org/10.1186/s12989-017-0199-z
- Tuckey, B., Srbely, J., Rigney, G., Vythilingam, M., & Shah, J. (2021). Impaired lymphatic drainage and interstitial inflammatory stasis in chronic musculoskeletal and idiopathic pain syndromes: exploring a novel mechanism. Frontiers in Pain Research, 2, 691740.
- Nakanishi, G., Pita-Oliveira, M., Bertagnolli, L. S., Torres-Loureiro, S., Scudeler, M. M., Cirino, H. S., … & Rodrigues-Soares, F. (2022). Worldwide systematic review of GSTM1 and GSTT1 null genotypes by continent, ethnicity, and therapeutic area. Omics: a journal of integrative biology, 26(10), 528-541.
- Stover, D. A., & Verrelli, B. C. (2011). Comparative vertebrate evolutionary analyses of type I collagen: potential of COL1a1 gene structure and intron variation for common bone-related diseases. Molecular biology and evolution, 28(1), 533-542.
- Schouw, M. E., Ruivenkamp, C. A., Koopmann, T. T., Santen, G. W., Nikkels, P. G., & van Der Tuin, K. (2025). A Deep Intronic Splice Variant in COL1A1 Causing Osteogenesis Imperfecta Type II. American Journal of Medical Genetics Part A, 197(5), e63972.
- Freiburg, C. D., Solomon-Degefa, H., Freiburg, P., Mörgelin, M., Bolduc, V., Schmitz, S., … & Wagener, R. (2023). The UCMD‐Causing COL6A1 (c. 930+ 189C> T) Intron Mutation Leads to the Secretion and Aggregation of Single Mutated Collagen VI α1 Chains. Human Mutation, 2023(1), 6892763.
- Pironon, N., Bourrat, E., Prost, C., Chen, M., Woodley, D. T., Titeux, M., & Hovnanian, A. (2024). Splice modulation strategy applied to deep intronic variants in COL7A1 causing recessive dystrophic epidermolysis bullosa. Proceedings of the National Academy of Sciences, 121(35), e2401781121.
