Ehlers-Danlos syndrome (EDS) is caused by genetic mutations that disrupt how your body builds and organizes collagen, the protein that gives structure and strength to your skin, joints, blood vessels, and organs. There are 13 recognized types of EDS, caused by defects in at least 20 different genes. The specific gene involved determines which type you have and how severe the symptoms are.
How Collagen Goes Wrong
Collagen is the most abundant protein in your body. Think of it as the scaffolding that holds your connective tissues together. In EDS, genetic mutations interfere with this scaffolding at one or more stages: the initial production of collagen, the assembly of collagen molecules into fibers, or the way those fibers organize into larger structures. The result is connective tissue that stretches too much, tears too easily, or simply doesn’t hold things in place the way it should.
Regardless of the specific gene involved, all types of EDS share a common thread: the collagen fibers end up with abnormal shape and organization. This explains why EDS affects so many different body systems. Collagen is everywhere, from your skin and joints to your blood vessel walls and digestive tract. When the building material is faulty, the structures made from it are faulty too.
Three fundamental mechanisms produce these collagen problems. First, the body may lack the enzymes needed to properly process collagen after it’s made. Second, a mutant collagen chain can get mixed in with normal chains during assembly, poisoning the final product (called a dominant-negative effect). Third, a mutation may simply cut collagen production in half, leaving the body without enough to work with (called haploinsufficiency).
The Genes Behind Each Type
Classical EDS, which affects roughly 1 in 20,000 to 40,000 people, is typically caused by mutations in the COL5A1 or COL5A2 genes. These genes provide instructions for making type V collagen, a form of collagen that helps regulate the diameter of collagen fibers in skin and other tissues. Rarely, mutations in COL1A1 can also cause this type.
Vascular EDS, the most dangerous form, results from mutations in the COL3A1 gene, which is responsible for type III collagen. This collagen is critical for the structural integrity of blood vessels, the uterus, and hollow organs like the intestines. People with vascular EDS have thinner blood vessel walls and increased mechanical stress on tissues that are already extremely fragile, which is why this type carries a risk of arterial and organ rupture. It’s rare, affecting about 1 in 100,000 to 200,000 people.
Classical-like EDS follows a different path entirely. Instead of a collagen gene, it’s caused by mutations in the TNXB gene, which makes a protein called tenascin-X. This protein isn’t collagen itself but plays a key role in collagen deposition, stability, and fiber formation. Tenascin-X is found in the heart, skin, skeletal muscle, ligaments, tendons, and digestive tract. When it’s missing, virtually all patients develop hyperextensible skin with a velvety texture, generalized joint hypermobility, and easy bruising.
Other rare types involve genes responsible for collagen-processing enzymes, proteins that cross-link collagen fibers, or molecules that help transport collagen out of cells. Each mutation affects a different step in the collagen pipeline, but the end result is always compromised connective tissue.
The Hypermobile EDS Mystery
Hypermobile EDS (hEDS) is by far the most common type, yet it’s the only one without a confirmed genetic cause. No single gene has been definitively linked to it, and no genetic test can confirm the diagnosis. This makes hEDS a clinical diagnosis, meaning doctors identify it based on symptoms, physical examination, and ruling out other conditions.
That doesn’t mean the search has stalled. A 2025 study using whole-exome sequencing of 200 hEDS patients identified rare variants in a family of genes called kallikreins, particularly a recurring mutation in KLK15. This gene codes for a protein that interacts with the extracellular matrix (the structural environment surrounding cells) and affects how connective tissue is remodeled. The variant appeared to disrupt how certain proteins are organized within this matrix, consistent with a dominant-negative effect.
This finding is significant because it reframes hEDS as something broader than a pure collagen defect. The KLK15 research suggests that matrix remodeling and immune signaling may also play a role, which could help explain why hEDS often comes with systemic symptoms like fatigue, digestive issues, and immune-related problems that seem unconnected to joint flexibility.
Separately, researchers have looked at the MIA3 gene, which helps transport connective tissue proteins out of cells. In a study of 100 hEDS patients, one patient carried a truncating mutation in MIA3 that cuts short a protein essential for collagen secretion. While a single case isn’t proof, it points to collagen transport as another potential mechanism worth investigating.
How EDS Is Inherited
Most types of EDS follow an autosomal dominant inheritance pattern, meaning you only need one copy of the mutated gene (from one parent) to develop the condition. Classical EDS, vascular EDS, and hypermobile EDS all fall into this category. If one of your parents has an autosomal dominant form, you have a 50% chance of inheriting it.
A smaller number of EDS types are autosomal recessive, meaning you need two copies of the mutated gene, one from each parent. Classical-like EDS caused by tenascin-X deficiency follows this pattern. Both parents must carry the mutation, and each of their children has a 25% chance of being affected.
Some cases arise from new (de novo) mutations, meaning neither parent carries the gene variant. This is particularly relevant in vascular EDS, where a person with no family history can develop the condition due to a spontaneous mutation in COL3A1 during early development.
Beyond Collagen: What Else Goes Wrong
The damage in EDS extends beyond the collagen fibers themselves. When the structural matrix surrounding cells is abnormal, cells can’t attach to their environment properly. In EDS, skin cells called fibroblasts have altered surface receptors and struggle to adhere to the defective matrix around them. This impaired cell adhesion compounds the structural weakness, because cells that can’t anchor properly also can’t maintain and repair tissue effectively.
Research using gene expression profiling has revealed that some EDS types also involve disrupted signaling inside cells. When misfolded collagen accumulates, it can trigger a stress response that further impairs cell function. Abnormal signaling through a pathway called TGF-beta, which regulates tissue growth and repair, has also been identified in some forms. These intracellular problems help explain why EDS symptoms often go beyond what you’d expect from a simple structural protein defect.
How EDS Is Identified
For most types of EDS, genetic testing can confirm the diagnosis by identifying the specific mutation. The exception, again, is hypermobile EDS. For hEDS, doctors rely on a set of clinical criteria updated in 2017 that include a physical assessment called the Beighton score.
The Beighton score tests five movements and assigns up to 9 points. You get one point for each side of the body where you can bend your pinky finger back past 90 degrees, touch your thumb to your forearm, hyperextend your elbow more than 10 degrees, or hyperextend your knee more than 10 degrees. One additional point is awarded if you can place your hands flat on the floor with your knees straight. The threshold for generalized joint hypermobility varies by age and sex, and falling just one point below the cutoff triggers a follow-up questionnaire rather than an automatic exclusion.
Meeting the hypermobility threshold alone isn’t enough for an hEDS diagnosis. The 2017 criteria also require specific features like unusually soft or stretchy skin, unexplained stretch marks, chronic pain, and a pattern of joint dislocations or instability, along with exclusion of other connective tissue disorders that can look similar.