This is day four of a five day series decoding the three most important studies from the past three years for five conditions. Last up: Long COVID. Up next: Ehlers-Danlos Syndrome.
A note before we begin. EDS encompasses 13 classified subtypes, most of which have known genetic causes. The exception, the one that affects the vast majority of EDS patients, is hypermobile EDS, or hEDS. It has no confirmed genetic cause, no biomarker, no blood test. Diagnosis rests entirely on clinical criteria. Patients are told their condition is genetic with no way to prove it. For decades, the molecular basis of hEDS has remained elusive. The three studies below represent the most significant progress toward changing that.
Study 1: The First Gene to Be Credibly Linked to hEDS, With a Mouse Model to Prove It
Gensemer C, Petrucci T, Beck T, et al. KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome. iScience. 2025;28(9):113343.
Published in iScience in September 2025 following peer review, this study began with whole-exome sequencing of 200 patients with hEDS. Whole-exome sequencing reads all the protein-coding regions of the genome, looking for rare variants that might explain a condition. The researchers were specifically looking for genetic variants that appeared across multiple unrelated hEDS families: variants rare enough to be potentially pathogenic but present consistently enough to suggest a shared biological mechanism.
They found rare and low-frequency variants in 14 out of 15 kallikrein genes across the cohort. The standout finding was a recurrent missense variant in KLK15, specifically p.Gly226Asp, which segregated in multiple unrelated families. A missense variant changes a single amino acid in the resulting protein, potentially altering its function. The fact that the same variant appeared independently in multiple families is a strong signal that it is not coincidental.
KLK15 encodes a secreted serine protease, an enzyme involved in cleaving proteins in the extracellular matrix. It is expressed in connective tissues, immune tissues, as well as in the scaffold surrounding cells. The protein interacts with fibronectin and lysyl oxidase, both components of collagen crosslinking and matrix organisation. Altered KLK15 function could subtly disrupt the molecular architecture of connective tissue throughout the body, which maps coherently onto the systemic manifestations of hEDS.
To test whether the KLK15 variant was actually driving tissue changes rather than simply correlating with them, the researchers created a knock-in mouse model carrying the equivalent mutation. This is the methodological step that elevates this study above correlation. The mice recapitulated hEDS features in tendons and cardiac valves, with observable connective tissue abnormalities. They also showed dysregulated cytokine profiles, with significant changes in inflammatory mediators including FGF21, IL-6, IL-4, CXCL10 among others. Each of these cytokines regulates inflammatory pathways, suggesting that a key consequence of the KLK15 variant is altered immune signalling alongside structural connective tissue changes.
This is not a complete genetic explanation for hEDS. KLK15 variants were found in a subset of patients, not all. hEDS is almost certainly genetically heterogeneous, meaning multiple different genetic mechanisms will eventually be identified across different patient subgroups. But this is the first time a gene has been credibly linked to hEDS in a peer-reviewed publication with a functional mouse model to support causality. It is a genuine landmark.
Study 2: The First GWAS of Hypermobile EDS
Petrucci-Nelson T, Guilhaumou S, Berrandou TE, et al. Complex genetics and regulatory drivers of hypermobile Ehlers-Danlos syndrome: insights from genome-wide association study meta-analysis. medRxiv preprint. September 2025. https://doi.org/10.1101/2025.09.19.25336146
I am a geneticist (and hypermobile, oh the irony). I conduct GWAS studies as part of my research. So this is a study I can speak about with some specificity, because the methodological choices made here matter enormously for interpreting what the findings actually mean. This is a preprint that has not yet completed peer review, which I am flagging clearly because it matters for how the findings should be interpreted.
A genome-wide association study scans millions of genetic variants simultaneously across cases and controls, looking for variants that appear more frequently in people with the condition. The key requirement is statistical power, driven almost entirely by sample size. hEDS has historically been impossible to study by GWAS because the sample sizes available were too small to detect common variants with modest effects above the genome-wide significance threshold of p<5x10⁻⁸.
This study addressed that problem through meta-analysis, combining three separate case-control studies to reach a total of 1,815 cases and 5,008 ancestry-matched controls. Meta-analysis pools summary statistics rather than individual patient data, which allows large effective sample sizes without requiring data sharing across centres. The analysis covered 6.2 million genetic variants using fixed-effects meta-analysis, complemented by gene-based association testing, transcriptome-wide association studies, along with integrative functional annotation across multiple tissues including nerve, skin and fibroblasts.
Two loci reached genome-wide significance. The primary locus is a regulatory region near ACKR3, the atypical chemokine receptor 3 gene on chromosome 2. Functional annotation of this locus showed that the risk alleles colocalize with expression quantitative trait loci in tibial nerve tissue specifically, alter enhancer activity and generate a transcription factor binding site. This implicates neuroimmune and pain signalling pathways in hEDS biology. ACKR3 is also required for heart valve development in animal models, a finding that may be relevant to the cardiovascular features reported by some hEDS patients.
The genetic correlation analysis is where some of the most striking findings emerge. Using LD-score regression, the study found significant genetic correlations between hEDS and ME/CFS, fibromyalgia, depression, anxiety, autism spectrum disorder, migraine and gastrointestinal diseases. As a geneticist I want to be clear about what this means and what it does not mean. Genetic correlation measures shared biological pathways between conditions, not shared identity. These correlations do not mean hEDS is the same condition as ME/CFS or that it is a mood disorder. They mean that the genetic variants associated with hEDS overlap meaningfully with those associated with these conditions, pointing toward shared biological mechanisms involving neuroimmune signalling, pain processing, together with autonomic regulation. For patients who have been told their ME/CFS, fibromyalgia, or anxiety is unrelated to their hEDS, this genetic architecture suggests otherwise.
As a geneticist, I also want to flag what this study cannot yet tell us. Two genome-wide significant loci from 1,815 cases is a starting point, not a complete genetic map. The genetic architecture of hEDS is almost certainly complex and polygenic, meaning many variants each contributing small effects. The sample size here is large enough to detect the strongest signals but will miss many others. The sample is predominantly of European ancestry, limiting generalisability. The preprint has not yet completed peer review. These are not reasons to dismiss the findings. They are reasons to hold them with appropriate scientific humility while the field builds on them.
Study 3: The PoTS-EDS Overlap Finally Quantified
Kwok CS, Hagger G, Gillespie D, et al. The co-existence of Ehlers-Danlos syndrome and postural orthostatic tachycardia syndrome: a systematic review of the literature. Autonomic Neuroscience. 2026;267:103453.
We decoded this study in detail in an earlier piece, so the description here will be more concise. Published in Autonomic Neuroscience in June 2026, this systematic review pooled 30 studies covering 8,421 patients with EDS and 12,983 patients with PoTS, producing the first properly quantified global picture of how frequently these two conditions co-occur.
The headline findings: PoTS occurs in 17.5% to 92.7% of EDS patients depending on the population studied. The largest study in the review, a 2025 international cross-sectional survey of 3,906 people with EDS, found that 52.7% had PoTS, with a twofold increased risk compared to those with hypermobility spectrum disorder alone. In the other direction, EDS occurs in 17.9% to 50% of PoTS patients.
The clinical implications are direct. Patients with both conditions carry a substantially greater medication burden, attend more clinic appointments, have worse gastrointestinal symptoms and have lower functional capacity than those with PoTS alone. The authors make a clear recommendation: if you have EDS, you should be screened for PoTS. If you have PoTS, you should be screened for EDS. The co-occurrence is too common to treat as coincidental or as a reason for specialist boundaries to prevent proper assessment.
This review matters for EDS specifically because it provides the statistical foundation for an argument the community has been making for years: these conditions are not separate issues requiring separate specialists who do not communicate. They are overlapping manifestations of shared biological vulnerability that require coordinated care.
Honourable Mentions
The hEDS proteomics study (Griggs M, Gensemer C, et al., ImmunoHorizons, 2025) identified 35 blood proteins that differed between 29 women with hEDS and 29 age-matched controls, confirmed in a validation cohort of 41 hEDS and 38 controls. Proteins involved in immune regulation and extracellular matrix function were among those differentially expressed, providing the first blood-based molecular signature of hEDS.
The AGA Clinical Practice Update (Lam C, et al., Gastroenterology, 2025) formally recognised, for the first time, that GI manifestations in hEDS are distinct and require structured clinical pathways. The guidance specifically addresses the interplay with PoTS and MCAS, providing a roadmap for patients who have cycled through GI clinics for years without answers.
The endometriosis-PoTS connection study (Chin et al., Autonomic Neuroscience, 2026) we decoded last week found that PoTS patients with endometriosis were nearly three times more likely to have EDS than those without endometriosis, with rates of EDS representing a 64 to 168-fold increase over general population estimates.
The Bigger Picture
Three years ago hEDS had no confirmed gene, no biomarker, no validated blood test, no molecular mechanism. Today there is a peer-reviewed mouse model implicating KLK15, a GWAS identifying the first genome-wide significant loci with neuroimmune and pain signalling implications, a genetic correlation map linking hEDS to ME/CFS, fibromyalgia, migraine, together with gastrointestinal disease at the genetic level, along with the largest quantification of the PoTS overlap ever published.
None of this yet provides a diagnostic test or a targeted treatment. But the scientific foundation is being built. The distance between what researchers now know about hEDS biology and what is reflected in most clinical consultations has never been wider. Closing that gap is the work of the next decade.
The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.
References
Gensemer C, Petrucci T, Beck T, et al. KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome. iScience. 2025;28(9):113343. https://doi.org/10.1016/j.isci.2025.113343
Petrucci-Nelson T, Guilhaumou S, Berrandou TE, et al. Complex genetics and regulatory drivers of hypermobile Ehlers-Danlos syndrome: insights from genome-wide association study meta-analysis. medRxiv preprint. 2025. https://doi.org/10.1101/2025.09.19.25336146
Kwok CS, Hagger G, Gillespie D, et al. The co-existence of Ehlers-Danlos syndrome and postural orthostatic tachycardia syndrome: a systematic review of the literature. Autonomic Neuroscience. 2026;267:103453. https://doi.org/10.1016/j.autneu.2026.103453
Griggs M, Gensemer C, et al. Proteomic discoveries in hypermobile Ehlers-Danlos syndrome reveal insights into disease pathophysiology. ImmunoHorizons. 2025;9(10):vlaf044. https://doi.org/10.1093/immhor/vlaf044
Lam C, et al. AGA Clinical Practice Update on diagnosis and management of immune and mast cell mediated GI conditions. Gastroenterology. 2025.
Chin AY, Rilinger RG, Levine M, et al. The endometriosis-POTS connection: a retrospective analysis. Autonomic Neuroscience. 2026;267:103469. https://doi.org/10.1016/j.autneu.2026.103469
This definitely excites me. Diagnosed hEDS and I can definitely say that what I have runs in my family…and has a good hard run there to boot. I have pelvic organ prolapse due to it and dealing with this had made me remember that I had an incident of rectal prolapse in a MALE family member growing up.