The Ehlers-Danlos syndromes (EDS) are a collection of 13 heritable connective tissue disorders. The most common is hypermobile EDS (hEDS), accounting for 90% of all EDS cases. For most forms of EDS, genetic testing can confirm a diagnosis. However, until today, there is no genetic test for hEDS. Without ‘hard evidence’, many hEDS patients have often faced skepticism from medical professionals.

Narrowing down a gene associated with hEDS has been historically tough, namely because patients with hEDS often experience a wide variety of symptoms such as:

• musculoskeletal pain
• gastrointestinal motility disorders
• autonomic dysfunction 
• immune dysregulation 
• mast cell activation syndrome
• chronic fatigue
• joint instability

A new study, led by Dr. Cortney Gensemer (an EDS patient herself), marks a real genetic breakthrough in hEDS research. Her study focused on the kallikrein (KLK) gene family, as this family of 15 genes are involved in numerous biological processes such as:

• extracellular matrix (ECM) 
• connective tissue integrity 
• vascular tone and autonomic regulation 
• inflammation
• endocrine signaling

What This Study Found

KLK Gene Variant Found in hEDS

The study conducted whole-exome gene sequencing (WES) on 200 individuals diagnosed with hEDS. Among these 200 individuals, 49 gene variants were identified across 14 of the 15 KLK genes, and 33.5% of participants carried at least one rare or uncommon KLK gene variant.

KLK15 Variant Runs in Families

Two families were looked at in this study. The first included four generations of individuals with hEDS (either diagnosed or strongly suspected). The second family consisted of just a mother and daughter. In both families, the KLK15 gene variant (p.Gly226Asp) was found in all those with hEDS. For instance, in the four-generation family, everyone with hEDS carried the KLK15 p.Gly226Asp variant, while everyone without hEDS did not. This is strong evidence that the KLK15 p.Gly226Asp variant is directly linked to hEDS in these families. 

[Chronic Pain Partners has reported on the initial findings here.]

KLK15 Found in Different Tissues Throughout the Body

In both humans and mice, the KLK15 gene was found to be present and active in many tissues: 

• glandular tissue (such as adrenals and thyroid)
• gastrointestinal tissue (such as colon and stomach)
• mast cells (a type of immune cell)
• anterior cruciate ligament (ACL) 
• dermal fibroblasts 

Many of these tissues are the same ones typically affected in hEDS and its co-morbidities.

KLK15 ‘Talks’ to Many Other Proteins

KLK15 interacts with 23 other proteins. Of these proteins, 10 were associated with the extracellular matrix (ECM), the body’s internal scaffolding or glue that holds tissues together and helps cells communicate. The other 13 proteins were associated with various processes such as immune function or signaling within cells. This means that variants of the KLK15 gene may have the potential to cause widespread dysfunction across multiple systems in the body.

Mice with KLK15 Variant Had Same Features Seen in People with hEDS

Genes of mice in this study were edited to make them carry the KLK15 p.Gly226Asp variant, the same variant found in the two families in this study. Mice with this variant displayed very similar features to those with hEDS, including thinner collagen fibers, weaker or more elastic tendons, heart valve dysfunction, and mitral valve prolapse. In addition to apparently disrupting their ECM, the KLK15 variant was also found to alter the signaling of the mice’s immune system.

What Does this Mean for hEDS?

The identification of the KLK15 variant (p.Gly226Asp) as a direct disease-causing gene in hEDS is a significant scientific breakthrough. This study also shows that this variant can cause both connective tissue dysfunction and immune system dysregulation. However, since only 33.5% of individuals with hEDS in this study carried a KLK variant, the findings suggest that hEDS most likely stems from multiple genes (both within and outside the KLK family) as well as possible environmental factors. While more research is clearly needed, this marks an exciting first step toward better diagnosis and treatment of hEDS in the future.

Jacqueline Teti, author and patient

with Hypermobility Spectrum Disorder

September 2025