Genetic Testing for the Ehlers-Danlos Syndromes

Does everyone need genetic testing? Can all types of EDS be diagnosed by a genetic test? What genes are involved?

If you’re reading this, it’s likely that you or a loved when have a diagnosis of one of the Ehlers-Danlos syndromes (EDS) or suspect that you might have it. Getting a diagnosis can be challenging, and information out there isn’t entirely straightforward when it comes to how to navigate the diagnostic journey. It’s actually so difficult for some, that entire papers (like this one) have focused solely on this journey.

Typically, when EDS is suspected, there is some discussion about seeing a geneticist or genetic testing from the suspecting healthcare provider. But genetics is confusing - there are 13 (or 14, depending on who you ask) subtypes of EDS, the hypermobility spectrum disorders (HSD), and in total 21 (ish?) genes involved, yet for some subtypes, we don’t know the genes. If you are asking yourself, “What?????”, you are not alone. In an attempt to make the messy genetics of EDS a little clearer, I have outlined all the different types of EDS, the genes involved, and some frequently asked questions below.

For a primer on genetics, head to my previous post where I discuss genetics and types of genetic testing. Understanding some key genetic terminology will be helpful for following the rest of this! This post has a lot of hyperlinks for additional reading as well.

Types of EDS, their inheritance pattern, and the genes associated with them:

(The below only includes a few major criteria and not the full picture of signs and symptoms for every subtype for the sake of being concise. For more details, check out this link on the EDS society website. )

• Classical EDS (cEDS): Autosomal dominant, hypermobile joints, skin hyperextensibility, and atrophic scarring. Caused by mutations in COL5A1 and COL5A2.

• Vascular EDS (vEDS): Autosomal dominant, arterial rupture at a young age, spontaneous colon perforation, uterine rupture, carotid-cavernous sinus fistula. Caused by mutations in COL3A1.

• Classical-like EDS (clEDS) Autosomal recessive, skin hyperextensibility, absence of atrophic scarring, hypermobile joints, easy bruising. Caused by mutations in TNXB.

• Myopathic EDS (mEDS): Autosomal dominant or autosomal recessive, muscle hypotonia, and/or muscle atrophy, proximal joint contractures, hypermobility of distal joints. Caused by mutations in COL12A1.

• Kyphoscoliotic EDS (kEDS): Autosomal recessive. Congenital muscle hypotonia, early onset kyphoscoliosis, generalized joint hypermobility with subluxations and dislocations. Caused by mutations in PLOD1 and KBP14.

• Musculocontractural EDS (mcEDS): Autosomal recessive, congenital contractures, characteristic craniofacial features, skin hyperextensibility, easy bruising, atrophic scars. Caused by mutations in CHST14 and DSE.

• Cardiac-valvular EDS (cvEDS): Autosomal recessive, cardiac-valvular problems (aortic valve, mitral valve), skin hyperextensibility, atrophic scarring, easy bruising and joint hypermobility of the small joints. Caused by mutations in COL1A1 and COL1A2.

• Arthrochalasia EDS (aEDS): Autosomal dominant, congenital bilateral hip dislocation, severe joint hypermobility with dislocation and subluxations, skin hyperextensibility. Caused by mutations in COL1A1 and COL1A2.

• Brittle Cornea Syndrome (BCS): Autosomal recessive, eye manifestations: thin cornea, keratoconus; keratoglobus, blue sclerae. Caused by mutations in ZNF469 and PRDM5.

• Dermatosparaxis EDS (dEDS): Autosomal recessive, extreme skin fragility and characteristic craniofacial features. Caused by mutations in ADAMTS2.

• Spondylodysplastic EDS (spEDS): Autosomal recessive, short stature, muscle hypotonia, bowed limbs. Caused by mutations in B4GALT7, B3GALT6, and SLC39A13.

• Periodontal EDS (pEDS): Autosomal dominant, dental manifestations: periodontitis, lack of attached gingiva, pretibial plaques. Caused by mutations in C1R or C1S.

• Classical-like EDS type 2 (clEDS2): Autosomal recessive, newly defined without major criteria but publications include: thin and hyperextensible skin, poor wound healing with prominent atrophic scarring, joint hypermobility, and cardiac manifestations. Caused by mutations in AEBP1.

• Hypermobile EDS (hEDS): Autosomal dominant, clinical spectrum of joint hypermobility, skin manifestations (milder than other subtypes), and specific symptoms of systemic connective tissue disorder, presence of comboridities*. Most common subtype of EDS. The genetic cause remains poorly understood. Work has been done to highlight roles of potential genes that have yet to be published, as well as a potential role for genes like LTZS1, and TPSAB1. The genetics of hEDS is complex and will not be explained by one single gene. Recent claims for the involvement of the MTHFR gene and others, lack data at this time to support the hypothesis.

*other subtypes may also present with similar comorbid conditions. comorbidities can include mast cell activation syndrome (MCAS), dysautonomia or postural orthostatic tachycardia syndrome (POTS), spinal instabilities, chronic pain, and additional neurological, immunological and endocrine dysfunction that is poorly understood.

If you want to do additional reading, this literature review has a more detailed description of the specific mutations in those genes that have been identified and the biological consequences.

I recognize that this can all feel a little overwhelming, and that’s why healthcare professionals like genetic counselors and geneticists can work with patients to explain the rationale for testing, inheritance, and what your results mean. But there are some common questions I’ve been asked over the last few years, so I’ve attempted to answer them the best I can below:

What happens if my genetic testing is normal?

All types of EDS except for hEDS and HSD are rare diseases. In most cases, genetic testing for these subtypes will be negative. That does not mean someone doesn’t have EDS. In this scenario, most physicians with experience in the EDS space will evaluate for clinical signs of hEDS - often using the 2017 diagnostic criteria as a guide. In other scenarios, depending on symptoms, a physician may clinically diagnose a rare subtype of EDS in the absence of a pathogenic variant. While this does occur, it is extremely uncommon.

What happens if my testing shows a variant of uncertain significance (VUS)?

This is a common topic of discussion on social media and in EDS communities. Simply put, a VUS means nothing. A VUS occurs when a change is detected in a gene that was included on a panel, and the effect of that mutation isn’t known. While additional research or testing family members could potentially help indicate the significance of the VUS, most of the time, a VUS stays a VUS for EDS and is not re-categorized. I talked about this a bit more in a previous instagram post.

Why are the same genes involved in multiple subtypes? Does that mean a mutation in COL1A1 causes someone to have multiple types of EDS at once?

Not exactly, when we are talking about a mutation in a gene, it doesn’t mean just any mutation. The exact nucleotide change or type of mutation is really important. Sometimes a deletion of a region of a gene has a different effect on than just switching out one letter for another (like changing an A to C at that allele). It also matters where the mutation occurs in the gene. A mutation in the beginning can have a completely different impact on the protein than a mutation in the middle of a gene.

Can someone be diagnosed with more than one type of EDS?

There are two parts to this question. Is it possible to have two types of EDS? Yes, it is. What is the chance this would actually happen? So incredibly rare it is probably not something that people need to worry about.

For someone to be diagnosed with two types of EDS, it would mean that both parents had a different type of autosomal dominant EDS, or that they were incredibly unlucky where each parent was a carrier for an autosomal recessive type of EDS, on top of one parent having an autosomal dominant type of EDS that they passed on. If we assume hEDS has a prevalence of 1 in 500 (based on our best estimate), and the next most common subtype is 1 in 20,000 for cEDS, the chance of a child being born with both cEDS and hEDS is about 1 in 10 million people. But within that hypothetical family, the chance would be a 1 in 4 chance of their child having both hEDS and cEDS.

So even with the most common types of EDS, this is incredibly unlikely that two people with two different types would end up having a child. Because of this, and the fact that hEDS does not have a genetic test at this time, if the child in this scenario were to have signs of EDS, and tested positive for cEDS genetically, they would likely only be given the cEDS diagnosis, because hEDS is a diagnosis of exclusion. If you look at even rarer types of EDS, the odds are even less likely.

Is it possible to have any other conditions that mimic EDS?

Lastly, there are other connective tissue disorders that can present similarly to EDS. So gene panels that encompass the broader umbrella of connective tissue disorders to include conditions like Marfan Syndrome, Loeys Dietz Syndrome, Homocystinuria, Cutis Laxa and Stickler Syndrome might be ordered by the physician as well. Check out this instagram post for other conditions that cause hypermobility.

What panels and genetic testing companies do you recommend?

Heritable Disorders of Connective Tissue Panel - GeneDx

Invitae Connective Tissue Disorders Panel

Invitae Ehlers-Danlos Syndrome Panel

These tests need to be ordered by a healthcare provider. Invitae also works with Genome Medical to set you up with a provider who can order testing online.

Does everyone with suspected EDS need genetic testing?

Technically, no. While 13 of the 14 subtypes of EDS can be diagnosed genetically, hEDS is diagnosed by a clinical checklist. However, because subtypes can overlap in symptoms, it is often a good idea for all suspected hEDS patients to get genetic testing. It helps providers and patients feel confident in the diagnosis when they know they haven’t missed anything!

If I had a connective tissue panel and there are new genetic discoveries for hEDS or HSD, will my results/data be useful?

Unfortunately, a gene panel will not be helpful for future genetic discoveries, because these panels only include known genes at this time. As discoveries are made, gene panels and genetic testing companies will add those new genes when they believe there is sufficient evidence and they have designed the assays to sequence them.

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