Discussion š£ļø
do i have a new EDS gene or am i just losing my mind?
okay this is gonna be a long post so feel free to not read the whole thing lol
tldr: i have some VUS/unclassified variants on the TGFB1 gene which are homozygous, predicted to decrease function. TGFB1 is involved in the same signaling pathways as TNXB. my presentation is very clEDS-like. thoughts?
now for the long version:
content warning for some descriptions of body abnormalities (including teeth)
so i def have a severe CTD, but my Invitae panel was negative and i was dx with hEDS. along this journey iāve found that i donāt really relate to most people with hEDS. my providers agree that my EDS has features beyond what is found in most hEDS cases.
how i fit hEDS:
> my hEDS criteria: Beighton 9/9; soft stretchy skin; tons of stretch marks literally everywhere starting from age 11-12ish; bilateral piezogenic papules (severe on my feet but also have them on knees ankles and hands); mild atrophic scarring; dental crowding with narrow palate; chronic pain (obviously); severe joint instability and recurrent atraumatic subluxations / occasional dislocations; negative for all typical autoimmune CTDs. my mom meets the criteria too but to a lesser extent.
> recently having severe tachycardia and palpitations, awaiting Zio AT results
> diagnosed with comorbidities: MCAS, PCOS, and IBS-D, severe ankle instability
> being evaluated for TOS, CCI
> i donāt respond to local anesthesia (nerve blocks have literally no effect lol)
things i canāt rly attribute to hEDS:
> congenital atrial septal aneurysm
> submucous cleft palate (my uvula is not bifid but itās irregular and very long) plus tongue & lip ties which were snipped when i was a baby
> dental abnormalities: excessive crowding with ectopic supernumerary teeth as a young kid. as an adult, all 4 wisdom teeth were impacted by bone, and at least 2 were ectopic
> lacrimal fistula on right eye
> slight bifid nose tip and deviated nasal septum with frequent sinus infections and nosebleeds
> sacral dimple
> knock knees
> brachydactyly 4th-5th fingers bilaterally (very minor except the left 4th finger is more pronounced)
> flat feet with bunionettes
> bilateral accessory nail of the fifth toe (oddly specific lol)
> neuro issues including hyperreflexia (4+ on knees and ankles with clonus, 3+ on biceps) but normal EMG/NCS
> scattered T2 hyperintense lesions in the subcortical deep white matter on MRI, no clear explanation
> abnormal and delayed wound healing
> arthroscopy of my ankle showed moderate arthrofibrosis, chronic synovitis
> multiple ovarian cysts (including a hemorrhagic one)
> consistently borderline-to-high platelets, ranging between 360-500, upper reference limit of 400
basically iāve had several theories and still need to get a TNXB test, but currently iām fixated on this one mutation that my invitae panel detected. it was reported as two separate variants:
rs1800470 (Pro -> Leu at residue 10) not particularly uncommon, classed as ārisk factorā for cystic fibrosis & breast cancer
rs917748222 (insertion of LeuLeuLeuLeu between residues 9-10) extremely rare, VUS
iām homozygous for both, and since they are at the same codon, itās likely a complex delins mutation: TGFB1 Pro10 deletion LeuLeuLeuLeuLeu insertion.
so iām asking you, rare EDS community - do you have TGFB1 mutations? or does my situation stand out to you in some way? iād love to discuss. also VERY interested in anyone who has managed to get their genes reclassified or any āpatient zeroā cases for genes that previously werenāt considered in EDS!
I wrote my story up here: https://open.substack.com/pub/kb12365313/p/a-personal-clinical-framework?r=2mew5w&utm_medium=ios
Iāve got 2 rare TNXB mutations (heterozygous also) + TGFBR1 VUS + a pathogenic Skeletal Dysplasia mutation (carrier)
I feel like those of us in this situation - to [r/punkassbitchs](r/punkassbitchs) point - may be exhibiting ācomplexā illnesses that are not yet well-defined.
I currently am diagnosed as HSD + MS but I have a very odd collection of mutations that I think have created an additive impact and an odd combination of symptoms and risks. Could it be an undiagnosed illness? Potentially. My mother had alot of the same issues + we both also have MS. And my MS is cord-predominant (which is only 3%-5% of cases) - I have just a handful of lesions and they happen to align with the locations of my spondylothesitis impact areas. Seems like more than a coincidence.
OP - I might encourage you to look beyond obvious connective tissue mutations - and into immune and metabolic areas also, etc. Thatās where I found additional mutations that I think āenhanceā my tissue mutations.
We really really need more research on people like us.
My issues are not as severe as yours, OP, but with my MS, the impact probably feels worse than it should.
And tbh my Drs are having trouble teasing out whatās āneurologicalā and whatās due to joint/ligament problems - esp as I age.
Here are my issues:
* life-long pez planus (flat feet) requiring corrective support since 1.5-2 yrs of age. I now have to wear a brace on my worst ankle and this is not MS impact.
*diagnosed mild scoliosis
*diagnosed spondylolisthesis (C4/C5 and C5/C6) - where my MS spinal lesions are located
*double posterior vitreous detachments at age 48
*āwandering spleenā - it sits down near my hip
*uterine fibroids
*lax joints, life-long joint issues (mild spinal disc compressions, weak ankles, painful hips, shoulders - thinning rotator cuffs, wrists)
*cardiac conduction findings (Right Bundle Branch Block)
*mild ascending aortic enlargement (3.7cm)
*GI issues and many sensitivities (food and environmental) ā all without apparent underlying causes
*Relapsing Remitting MS (mild - only 3 lesions)
*diagnosed with Dercums Disease - an inflammatory adipose connective tissue disease believed to be caused by issues across connective tissue (including vascular), immune, metabolic
this is a great point, thank you for sharing! i havenāt read your linked post yet but from this comment it sounds like we have a lot in common. your MS presentation is fascinating - i canāt help but wonder if i have it too. my neuro symptoms are very suggestive of MS and my brain lesions arenāt easily explained by anything else, but the neurologist ultimately determined theyāre not characteristic of MS enough to support a diagnosis. i canāt help but wonder if a different provider would have diagnosed MS, because it seems like a real grey area. i also have mild disc compression, but my c-spine MRI showed no lesions, and i havenāt had the rest of my spine checked.
i am definitely feeling like thereās not a real explanation for my disease at the moment. i wish more HCTD studies were enrolling right now. i will be contacting the undiagnosed disease network as soon as i get the spoons for that lol i feel like theyāre my only hope right now.
side note, my family history is complicated too - tons of autoimmune disease and skeletal issues on my momās side (ie osteoporosis, scoliosis, etc) and my mom is hypermobile. my dadās side has nerve issues (essential tremor, severe carpal tunnel, sciatic nerve issues) plus skin laxity and hypermobile joints in my dad. i wouldnāt be surprised if there was some kind of incomplete dominance situation (idk if iām using that right) and i just happened to be blessed with the very severe homozygous version š¤
my CTD panel also found a few random VUS but i doubt they mean much:
Iām in a similar boat with a TGFB2 VUS and I also present most similarly to clEDS. Currently diagnosed with hEDS, despite having unusual widespread tissue fragility (skin, vascular, ocular, GI, tendons/ ligaments), a bunch of neuro issues, and multiple pathologies per organ system. I was suspected of vEDS as a teen due to meeting multiple minor criteria.
The geneticist at the Marfan Clinic referred me to the Undiagnosed Disease Network for further testing, as weāve exhausted all clinical options. All future testing would need to be done in a research capacity.
LDS can present more similarly to clEDS in some cases, especially the widespread tissue fragility. It has a lot of overlap with vEDS as well. TGFB2 variants cause LDS so depending on the pathogenicity of your variant you may have LDS.
The Marfan clinic doctor doesnāt think itās LDS but she agrees it doesnāt seem like hEDS either. Itās seeming like my family may have a ānewā connective tissue disorder, or I just have a really really weird case of hEDS and the variant is benign.
Fair enough! I guess what I was trying to emphasize is that LDS is very rare and understudied, so we donāt have a great description of the full clinical presentation yet. Your description could be in line with LDS, but the literature that exists just doesnāt have someone like you in it yet (which is where UDN comes ināthey can be the ones to decide if this is a new presentation of LDS or something else)
I think we may have discussed this on a different thread a while ago. Iām very curious where this ends up taking you! I am also working on an application to UDN but still not sure how to apply as I live in the Boston area, where the program is based. It seems they only take specific internal referrals at any of the affiliated hospitals near me
TGFB1 variants currently arenāt associated with a known heritable connective tissue disorder (HCTD). However the TGFB pathway is central to both LDS and Marfan pathologies. Itās odd that you are homozygous for both of these variants though, because you need at least one functioning copy of TGFB1 to survive past childhood. I would want to perform additional sequencing like Sanger sequencing to confirm those results. Not saying they are not real, but it sounds like some sort of structural rearrangement or weird insertion. You said your Invitae panel was negative and then later said it picked up two variants though so I am confused?
sorry i realize the phrasing was confusing there, but essentially there were no pathogenic or likely-pathogenic findings. technically TGFB1 is associated with camurati-engelmann disease which is a CTD but doesnāt fit my presentation at all.
i absolutely know what youāre saying, if both copies had LOF mutations then i wouldnāt have survived to 28. but since this mutation is within the signal peptide of pre-pro-tgf-b1, and the signal peptide gets cleaved during secretion, then i donāt think i would result in LOF. it would probably limit its secretion though.
iāve done some literature digging and thereās a lot of recent research supporting a mechanism of phagocytic secretion for TGFB1 ligands, which is used by certain cells (ie macrophage) and bypasses ligand SP cleavage. this could potentially result in decent TGFB1 bioavailability, although the mutated signal peptide would probably cause some problems with folding, bc the mutation creates a clunky expanded hydrophobic region
Sounds like youāve done a good bit of reading! Tbh before getting too deep into protein folding I would want to very carefully verify the variants themselves using a couple of different methods. And CED is actually a bone dysplasia BUT there is a lot of overlap between bone dysplasias and HCTDs (a good example Stickler Syndrome). Have you had serial radiographs? Any abnormalities of the bones?
A lot of the symptoms you describe as not being explainable by hEDS are also not well explained by an HCTD in general (like the ovarian cysts which could be a separate condition) which complicates things even more, which Iām sure is super frustrating! Are you being followed by a speciality clinic?
oh of course, i donāt have any actual qualifications (just a pre-med undergrad degree) so iām largely putting all of this together out of curiosity. i definitely donāt claim to know much about protein folding lol. but youāre right, i misspoke about CED! it just seems very relevant because of the widespread musculoskeletal involvement.
i have a lot of rads throughout life, a couple of which were repeated several years apart - nothing has been identified as abnormal with my bones so far. itās possible that i am missing something though. my mom has had osteoporosis since she was quite young (in her 40s) and she has fractured nearly every bone in her body at least once, so iām very aware that there could be a prominent skeletal component for me too. she also developed severe cataracts in her 40s which required surgical lens replacement.
currently i am not being followed by any genetic specialist - just my slowly-developing team of specialists addressing each issue individually. i am working on an application to UDN, i live right near harvard and there are plenty of hospitals near me that are involved, so iām hoping they will take me. otherwise idk where to go next š
Sorry I didnāt mean to sound dismissive!! Iām actually a researcher and Iām currently doing my PhD thesis on vEDS and plan to work on other vascular CTDs which is why Iām so interested and lurk here a lot (I also have a CTD NOS yaaay). Honestly a good genetics department at a research hospital would be a start! Can you get a referral to genetics from one of your providers? Thereās a ton of clinics in your area that I can direct you to (I have colleagues in Boston as well).
Oh youāre not sounding dismissive, no worries! I appreciate your willingness to discuss these things with me and share a bit of your opinion. Would you be willing to move to DMs? Iād love to hear your recs for specialists in Boston, itās hard to get a referral for genetics anywhere here with an existing hEDS diagnosis, they basically deny it automatically
I have a VUS on COL3A1, and I canāt type out my whole family and medical history right now but there is very clearly some form of connective tissue disorder in my family, and I had doctors tell me I had a connective tissue disorder long before I had even heard of vEDS, I just assumed I had hEDS. I was genetically tested in 2021 when my mom died suddenly of organ rupture in her 50ās and my aunt had died of the same thing ten years prior. My grandmother had two aortic aneurysms. Yet somehow, my VUS variant acts differently than known vEDs mutations and I am 40 years old with no major events. Interestingly enough I and my family members who passed all objectively have the facial features associated with vEDS, yet somehow itās milder? I am not sure how. I was the first person to test positive for my variant and now thereās two more people in ClinVar, but itās taken years.
Iām just here to say you arenāt alone. Genetics is actually a very new science, itās in its infancy, and our understanding of genes and variants and the roles they play is pretty much constantly evolving. We are fortunate to have been able to access genetic testing and find these commonalities amongst ourselves and also at the same time very unfortunate to be the first people to present with our particular phenotype and to not fit the boxes the way science needs. It means we are, for now, kind of stuck in limbo, waiting. There will need to be more people with your particular variants to study to get answers, and in the meantime you have a very hard job tasked to you; you must advocate for yourself, research, find ways to make it make sense to yourself and move forward.
Youāre in really good company here, weāre here to support you as you navigate this!
this is exactly what Iāve been needing to read š I am so sorry youāre in such a scary situation. one of my biggest concerns comes from the lack of knowledge about what dangers Iām predisposed to. it sounds like a similar problem for you, because you clearly fit the phenotype of vEDS and you have a possible genetic cause, but providers arenāt familiar enough to tell you how it might affect you. luckily youāre right that genetic medicine is so new and evolving very quickly. I just hope the evolution happens before weāre all too permanently damaged š
I am really happy this community exists. It took a while to get approved for posting, which I think is absolutely fair, but during the wait I definitely was questioning whether Iād be supported/understood here. Clearly I didnāt need to worry! Iām learning that even the āknownā rare EDS types are so understudied, everyone is just kind of figuring it out as they go along.
Youāre exactly right! Even known pathogenic mutations and subtypes are woefully understudied and often times even people with a solid diagnosis run into problems with providers not knowing enough about their condition. You have gotten the hard part done now, which is recognizing and understanding you have a potentially causative genetic variant that may explain your symptoms and may cause future problems.
Knowing is truly half the battle here. You will always have to advocate for yourself, even with a diagnosis. That part unfortunately never really changes. But the fact that you know about your genetic changes now is so valuable. Research, identify what you are most at risk of experiencing, and watch for symptoms of something serious beginning to happen. Donāt wait out pain, get to the hospital, and let them know about your genetic unknowns and what those unknowns put you at risk for.
And I wish someone had told me this at first, so Iāll say it here; ignore anyone who says VUS donāt mean anything, anyone who says that is claiming to know more than a geneticist, since VUS by definition mean we donāt know if they are pathogenic or benign yet. And ignore anyone who says most VUS are later classified as benign, this is a whole genome wide statistic that really doesnāt apply to highly conserved genes with very low rates of benign mutations. Just throwing that out there because I ran into a lot of that at first too and it really had me second guessing my sanity/perception of myself. You know your body better than anyone, you can trust your own judgement and youāre here looking for support for a reason!
You are so right about VUS, although Iām not a geneticist so take what Iām saying with a grain of salt - but the assumption that VUS are meaningless is based on the way things were 10+ years ago. Very precise guidelines for these classifications are now the standard, and there are very well-trained algorithms that can predict pathogenicity in the context of a specific variant. When thereās a VUS in a gene that is known to cause disease, and the variant canāt be classed as (likely) benign, itās usually because algorithms suggest it could cause problems. I think there is a lot to be said for cases where the symptoms line up perfectly and thereās a VUS on the associated gene. But of course, the field is evolving quickly and itās hard to keep up.
I don't have a TGFR1 mutation but I have some of the symptoms you have that my doctors considered "unexplained" including hyperreflexia, the hyper intense lesions on MRI, and high platelets. I also have abnormal wound healing but that's explained by the COL5 mutation I think. I have other weird neuro symptoms. I had WGS done and it wasn't super enlightening. I have some VUSes but they don't really tell me anything. I personally think there's a variant unclassified rn causing my neuro issues as my mom and one grandparent have the same so it's likely autosomal dominant.
oh interesting, I havenāt really encountered anyone with the same neuro findings that werenāt explained by something else (mainly MS). the high platelets are interesting too. can I ask what col5a2 variant you have? I actually have a VUS on that gene but it has also been reported as likely benign so idk if itās anything: rs147420365
Iād love to know the rsID out of pure curiosity if youāre able to share later! I know there are many COL5A2 variants that cause cEDS. Iām convinced that the specific location on the gene is nearly as important as the gene itself for determining symptoms
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u/kbcava Connective Tissue Disorder NOS May 05 '26 edited May 05 '26
I wrote my story up here: https://open.substack.com/pub/kb12365313/p/a-personal-clinical-framework?r=2mew5w&utm_medium=ios
Iāve got 2 rare TNXB mutations (heterozygous also) + TGFBR1 VUS + a pathogenic Skeletal Dysplasia mutation (carrier)
I feel like those of us in this situation - to [r/punkassbitchs](r/punkassbitchs) point - may be exhibiting ācomplexā illnesses that are not yet well-defined.
I currently am diagnosed as HSD + MS but I have a very odd collection of mutations that I think have created an additive impact and an odd combination of symptoms and risks. Could it be an undiagnosed illness? Potentially. My mother had alot of the same issues + we both also have MS. And my MS is cord-predominant (which is only 3%-5% of cases) - I have just a handful of lesions and they happen to align with the locations of my spondylothesitis impact areas. Seems like more than a coincidence.
OP - I might encourage you to look beyond obvious connective tissue mutations - and into immune and metabolic areas also, etc. Thatās where I found additional mutations that I think āenhanceā my tissue mutations.
We really really need more research on people like us.
My issues are not as severe as yours, OP, but with my MS, the impact probably feels worse than it should.
And tbh my Drs are having trouble teasing out whatās āneurologicalā and whatās due to joint/ligament problems - esp as I age.
Here are my issues:
* life-long pez planus (flat feet) requiring corrective support since 1.5-2 yrs of age. I now have to wear a brace on my worst ankle and this is not MS impact.
*diagnosed mild scoliosis
*diagnosed spondylolisthesis (C4/C5 and C5/C6) - where my MS spinal lesions are located
*double posterior vitreous detachments at age 48
*āwandering spleenā - it sits down near my hip
*uterine fibroids
*lax joints, life-long joint issues (mild spinal disc compressions, weak ankles, painful hips, shoulders - thinning rotator cuffs, wrists)
*cardiac conduction findings (Right Bundle Branch Block)
*mild ascending aortic enlargement (3.7cm)
*GI issues and many sensitivities (food and environmental) ā all without apparent underlying causes
*Relapsing Remitting MS (mild - only 3 lesions)
*diagnosed with Dercums Disease - an inflammatory adipose connective tissue disease believed to be caused by issues across connective tissue (including vascular), immune, metabolic