The invisible condition affecting 1 in 5,000 people is finally revealing its molecular secrets
Imagine a medical condition so pervasive that it affects nearly every system in your body—from the flexibility of your joints and the stretchiness of your skin to your digestive function, heart rate regulation, and even how you experience pain. Now imagine that despite affecting an estimated 1 in 5,000 people, this condition has no confirmed genetic test, leaving patients navigating skepticism and uncertainty. This is the reality for individuals with hypermobile Ehlers-Danlos syndrome (hEDS), the most common yet most mysterious form of Ehlers-Danlos syndrome 1 6 7 .
hEDS affects multiple body systems but lacks a definitive genetic test, creating diagnostic uncertainty.
Recent research is uncovering the genetic basis of hEDS, rewriting our understanding of this complex condition.
The Ehlers-Danlos syndromes comprise a group of 13 heritable connective tissue disorders, with hEDS accounting for approximately 90% of all cases 7 . What sets hEDS apart from other EDS subtypes isn't just its prevalence but its genetic elusiveness.
| EDS Type | Genetic Basis | Inheritance Pattern |
|---|---|---|
| Classical EDS (cEDS) | COL5A1, COL5A2, COL1A1 | Autosomal Dominant 8 |
| Vascular EDS (vEDS) | COL3A1 | Autosomal Dominant 8 |
| Arthrochalasia EDS (aEDS) | COL1A1, COL1A2 | Autosomal Dominant 8 |
| Dermatosparaxis EDS (dEDS) | ADAMTS2 | Autosomal Recessive 8 |
| Hypermobile EDS (hEDS) | Unknown | Presumed Autosomal Dominant 6 |
For most EDS types, genetic testing can confirm a diagnosis by identifying pathogenic variants in genes responsible for collagen production or processing. Collagen serves as the fundamental scaffolding that provides strength and structure to connective tissues throughout the body. When this scaffolding is compromised, the resulting fragility manifests as the various symptoms of EDS 5 8 .
hEDS, however, presents a different story. Despite sharing many clinical features with other EDS types—including joint hypermobility, soft and stretchy skin, and tissue fragility—no single gene has been consistently identified as its cause 6 .
Without a genetic test, how do clinicians diagnose hEDS? The International Consortium on Ehlers-Danlos Syndromes established strict clinical criteria in 2017 that must be met for diagnosis 6 .
Measured by a specific Beighton score (typically ≥5 for adults up to age 50)
Evidence of systemic connective tissue disorder manifestations, positive family history, or musculoskeletal complications
Elimination of other conditions that could explain the symptoms
This clinical diagnosis is further complicated by hEDS's association with numerous comorbid conditions that extend far beyond joint problems, including chronic fatigue, functional bowel disorders, cardiovascular autonomic dysfunction, anxiety disorders, and mast cell activation disorders 6 .
The year 2025 has brought significant breakthroughs in hEDS research, with two major studies identifying potential genetic contributors to this complex condition.
First evidence of common genetic variants contributing to hEDS risk 2 .
New candidate genes identified with functional validation 7 .
The KLK15 research provides a fascinating case study of how scientists move from genetic association to functional confirmation—a critical process in establishing a gene's role in disease.
Researchers began with whole-exome sequencing of 200 hEDS patients, identifying KLK gene variants in a substantial subset of participants 7 .
The research team identified two families with multiple affected members and demonstrated that the KLK15 p.Gly226Asp variant was present in all affected individuals and absent in unaffected relatives 7 .
Scientists determined where the KLK15 gene is normally active in both human and mouse tissues, finding it in precisely the tissues affected in hEDS: glandular tissue, gastrointestinal organs, mast cells, ligaments, and skin fibroblasts 7 .
Using gene-editing technology, researchers introduced the exact human KLK15 variant (p.Gly226Asp) into mice 7 .
The team conducted detailed analyses of the genetically modified mice, documenting their connective tissue structure, tendon function, and cardiovascular health 7 .
This experiment was particularly significant because it moved beyond correlation to demonstrate causation—the gold standard in genetic research. The findings suggest that KLK15 variants can disrupt both connective tissue integrity and immune system function, creating the multisystem manifestations that characterize hEDS 7 .
| Research Tool | Function in hEDS Genetic Research |
|---|---|
| Whole Exome Sequencing | Captures the protein-coding regions of the genome to identify rare variants 7 |
| Genome-Wide Association Study (GWAS) | Identifies common genetic variants associated with disease across the entire genome 2 |
| Genetically Modified Mouse Models | Allows researchers to study the effects of specific genetic variants in a living organism 7 |
| eQTL Analysis | Reveals how genetic variants affect gene expression in different tissues 2 |
| Protein-Protein Interaction Mapping | Determines how proteins encoded by candidate genes interact with other proteins in the cell 7 |
The emerging genetic picture of hEDS reveals extraordinary complexity. Rather than being caused by a single gene, hEDS appears to be a polygenic condition—resulting from the combined effects of multiple genes, both within and outside the KLK family, potentially influenced by environmental factors 2 7 .
Each new gene identified offers potential targets for future treatments
Bringing us closer to the day when a genetic test might be available
Approaches that address not just symptoms but underlying causes
Perhaps most importantly for patients, these genetic advances validate what they've known all along—that hEDS has a biological basis, even if it's complex and multifaceted.
While the journey to fully understand hEDS genetics is far from over, each discovery adds another piece to the puzzle, creating hope for millions affected by this invisible yet profoundly impactful condition.