This is day one of a five day series. Each day this week I am publishing a piece decoding the three most important studies from the past three years for a different condition. Today: PoTS.
The criteria were simple. The study had to be published between 2023 and 2026. It had to produce genuinely new knowledge rather than confirm what we already suspected.
Of course there are a lot of important research articles and all of the work is valuable as it aids advance our understanding… this is just my opinion!
Study 1: The First Genetic Map of PoTS
Qu H, Qu J, Chang X, et al. The genetic landscape of pediatric postural orthostatic tachycardia syndrome. Clinical Autonomic Research. 2025;35:431–451.
I am a geneticist and I conduct GWAS studies as part of my research. So when the first genome-wide association study of PoTS was published in February 2025, I read it differently to most people who cover this condition. And I want to explain exactly what was done, what was found, and why it is more significant than the headline numbers might suggest to someone without a genetics background.
A genome-wide association study, or GWAS, is a method for scanning the entire genome across large numbers of people with and without a condition, looking for genetic variants that appear more frequently in those with the condition. It is one of the most powerful tools in modern genetics, and it has transformed our understanding of conditions from schizophrenia to type 2 diabetes. But it has a fundamental requirement: a large, well-defined, homogeneous patient population. The bigger and cleaner the cohort, the more power the study has to detect signal above the statistical noise.
PoTS presents a specific challenge for GWAS that the authors address head-on. The condition is heterogeneous. Neuropathic PoTS, hyperadrenergic PoTS, hypovolemic PoTS, post-viral PoTS, they all meet the same diagnostic criteria but likely have different underlying mechanisms and therefore different genetic architectures. Running a GWAS on a mixed bag of subtypes is like trying to find the genetic signature of chest pain, the signal gets diluted by the heterogeneity before you can detect it. The authors acknowledge this directly and design their analysis accordingly.
Rather than trying to identify individual genome-wide significant loci, which would require sample sizes far beyond what was available for this rare condition, they took a gene-set analysis approach. Instead of asking which single genetic variant is associated with PoTS, they asked which biological pathways are enriched in PoTS patients. This is statistically appropriate and, in my view, the correct methodological choice for a phenotypically heterogeneous condition at this stage of genetic investigation.
The study recruited from the POTS Program at the Children’s Hospital of Philadelphia, one of the largest specialist paediatric PoTS programmes in the world. Two cohorts were used: a family cohort of 100 complete families and a case-control cohort of 207 unrelated cases compared with 4,063 ethnicity-matched controls. The whole exome sequencing component included 87 unrelated cases and 2,719 controls.
The common variant analysis identified 5,670 SNPs with nominal significance in both cohorts, pointing in the same direction. While none reached traditional genome-wide significance individually, 716 genes showed association at the gene level, far more than the 53 expected by chance. The over-representation analysis of those 716 genes pointed to gene sets involved in cell-cell junctions, synaptic membranes, transporter complexes, and early estrogen response as statistically enriched pathways in PoTS.
The estrogen response finding is particularly interesting. PoTS affects women at rates of up to 5 to 1 compared to men, and the connection with female sex hormones has been clinically observed but poorly understood at a molecular level. Finding early estrogen response genes overrepresented in a PoTS GWAS dataset provides a first molecular signal that the hormonal vulnerability of this condition may have a genetic basis.
The whole exome sequencing analysis was where the most striking findings emerged. By looking specifically at rare coding variants, the kind that have a larger individual effect on gene function but are too uncommon to detect by standard GWAS, the study identified 55 genes with genome-wide significance through burden analysis. These 55 genes tell a story that is coherent with what we know about PoTS clinically.
32 of the 55 genes are related to muscular function, specifically contractile fibre structure, extracellular matrix components, and cell-substrate junctions. This points toward skeletal muscle dysfunction, particularly in the calf muscle pump that drives venous return from the lower limbs, as a potential genetic contributor to PoTS. The calf muscle pump is one of the main mechanisms for pushing blood back toward the heart when standing. If its genetic architecture is subtly impaired in some PoTS patients, that would contribute directly to venous pooling on standing.
Multiple dynein axonemal heavy chain genes (DNAH1, DNAH2, DNAH3, DNAH10) appeared in the enriched gene sets, pointing toward microtubule dysfunction. Endothelial cell cilia, which depend on proper microtubule function, are increasingly recognised as sensors of blood flow. Dysfunction in endothelial cilia has been linked to vascular disorders including hypertension, and may contribute to the impaired vascular reactivity seen in PoTS.
43 of the 55 genes are associated with autism spectrum disorder in the GWAS catalog. This is a striking finding. Autonomic dysfunction is common in ASD, and there is increasing clinical recognition of co-occurrence between PoTS and neurodevelopmental conditions. The genetic overlap suggests a shared biological substrate that has implications both for understanding the aetiology of PoTS and for how we support patients who present with both conditions.
The limitations of this study are real and the authors are honest about them. The paediatric cohort from a single centre may not represent all PoTS presentations. The sample size limits the statistical power for individual variant detection. And the focus on European ancestry means findings may not generalise to other populations. Larger, multi-ancestry, multi-site GWAS studies in PoTS are urgently needed, and the findings here provide the gene-set hypotheses that future larger studies should explicitly test.
But this is the first genuinely systematic genetic investigation of PoTS, conducted with appropriate methodology for a heterogeneous condition, and its findings are biologically coherent with what we know. It is the starting point for the genetic understanding of this condition. A full dedicated piece decoding this study in even more detail is coming to Dysautonomia Decoded soon.
Study 2: The First Brain Scan Evidence That Brain Fog in PoTS Is Measurable
Seeley MC, et al. Novel brain SPECT imaging unravels abnormal cerebral perfusion in patients with postural orthostatic tachycardia syndrome and cognitive dysfunction. Scientific Reports. 2025;15:3487.
Brain fog is one of the most consistently reported and most consistently dismissed symptoms in PoTS. Researchers at the University of Adelaide used brain SPECT imaging in 56 PoTS patients who reported cognitive symptoms and found that 61% showed abnormal cerebral blood flow patterns. The regions most affected were the prefrontal cortex and sensorimotor cortex, the areas responsible for attention, decision-making and memory. Critically, abnormal perfusion was present even while patients were lying flat, not just on standing.
When the researchers modelled what was driving quality of life, the number of brain regions with abnormal blood flow accounted for 51% of the variance. Standing heart rate, the measure used to diagnose PoTS, accounted for none of that variance independently.
Brain fog is not a mood. It is measurable, visible on imaging, and directly linked to reduced cerebral perfusion. A full piece on this study is available on Dysautonomia Decoded.
Study 3: The Plasma Proteomics Study That Found 393 Differentially Expressed Proteins
Johansson M, et al. Plasma proteomics in postural orthostatic tachycardia syndrome reveals hypercoagulability, complement activation and increased adrenergic tone. Frontiers in Cardiovascular Medicine. 2023.
While study one addresses genetics and study two addresses brain imaging, this study went to the blood. Researchers from Lund University and the Karolinska Institute performed proteomics analysis on plasma samples from PoTS patients and matched healthy controls, identifying 393 differentially expressed proteins.
The PoTS samples showed evidence of a hypercoagulable state, complement activation, and increased adrenergic activity at the molecular level. This is not symptom data or imaging data. It is direct molecular evidence that PoTS is associated with measurable biological differences in the blood, spanning coagulation, immune activation, and autonomic signalling simultaneously.
The findings suggest that PoTS is not simply an autonomic condition with cardiovascular consequences. It involves broader systemic dysregulation that is detectable in the blood protein landscape. This also raises the genuine possibility that blood-based biomarkers could eventually be used for diagnosis or subtype stratification, though that work is at an early stage.
Honourable Mentions
Two other studies from this period have their own dedicated pieces on Dysautonomia Decoded.
The tilt table versus active stand comparison (Stiles, Raj et al., Autonomic Neuroscience, 2025) found that the same diagnostic threshold catches 98% of confirmed PoTS cases during a head-up tilt test but only 74% during an active stand test. Patients may receive very different results depending solely on which test they get.
The diagnostic bias study (Sediqi et al., JGIM, 2026) gave 1,027 physicians identical PoTS cases with only patient demographics changed. PoTS had the lowest diagnostic accuracy of all five conditions tested. Male physicians correctly diagnosed it in just 41.7% of cases.
The Bigger Picture
Three years ago the evidence base for PoTS was thin. The studies above represent a field genuinely moving in the right direction. Genetics is beginning to map inherited risk and biological pathways. Brain imaging is showing measurable neural abnormalities. Proteomics is identifying molecular signatures in the blood. And clinical research is documenting the systemic barriers that prevent patients from being diagnosed.
There is still no approved treatment for PoTS. The average diagnostic delay is still 7 years. But the science has never been more active, and the distance between where the research is and where clinical practice is has never been clearer.
The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.
References
Qu H, Qu J, Chang X, et al. The genetic landscape of pediatric postural orthostatic tachycardia syndrome. Clinical Autonomic Research. 2025;35:431–451. https://doi.org/10.1007/s10286-025-01110-2
Seeley MC, et al. Novel brain SPECT imaging unravels abnormal cerebral perfusion in POTS. Scientific Reports. 2025;15:3487. https://doi.org/10.1038/s41598-025-87748-4
Johansson M, et al. Plasma proteomics in postural orthostatic tachycardia syndrome. Frontiers in Cardiovascular Medicine. 2022. doi: 10.1038/s41598-022-24729-x
Stiles LE, Raj SR, et al. Physiological and clinical comparison of active stand and head-up tilt tests in POTS. Autonomic Neuroscience. 2025. https://doi.org/10.1016/j.autneu.2025.103281
Sediqi S, et al. Assessing the role of patient-physician sex concordance on diagnostic accuracy in primary care. Journal of General Internal Medicine. 2026. https://doi.org/10.1007/s11606-026-10670-6
I have spent years watching medicine divide the body into departments while my body stubbornly refuses to respect the filing system.
I’m 42, AuDHD, I suspect PoTS and hEDS, I’ve had severe endometriosis since I was 12, and I’m now in medically induced perimenopause because of it. So the genetic overlap with autism, the estrogen-response signal, the muscle/connective-tissue findings, and the broader systemic picture of PoTS are fascinating to me in a very personal way.
Not because I think this study has suddenly explained me.
It hasn’t.
But because it suggests that some of the connections patients have been noticing in their own bodies may actually be worth investigating biologically instead of being dismissed as an improbable collection of unrelated complaints.
I still can’t get through Swedish primary care to the specialists who investigate PoTS and hEDS, which makes the gap between research and clinical reality painfully literal for me.
But I am genuinely excited. The map is still incomplete, but at least science is finally starting to draw the roads.
And I have to say: this must have taken an absolutely monumental amount of work. Thank you for researching, decoding, and bringing all of it together so thoughtfully.
I have a question that maybe you can help with. Would estrogen affect a transgender male to female person. This person developed POTS following commencement of estrogen.
Thanks.