Background: Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSDs) are prevalent, complex conditions marked by chronic pain, joint instability, and multisystem involvement. Despite affecting an estimated 1 in 500 individuals, these conditions remain poorly understood and inconsistently diagnosed. This study aimed to define their clinical burden through a large-scale, international survey. Methods: A cross-sectional, anonymous survey was distributed globally from September 2023 to March 2024. Of 9258 responses, 3906 met inclusion criteria (hEDS: n = 3360; HSD: n = 546). The 418-item questionnaire assessed symptoms, comorbidities, healthcare utilization, and quality of life. The 95% confidence intervals (CIs) were calculated for comparison. Results: Participants with hEDS reported a mean of 24 comorbid conditions and an average diagnostic delay of 22.1 years. Common diagnoses included gastrointestinal disorders (84.3% [95% CI: 98.3–99.2%]), dysautonomia (71.4% [95% CI: 69.9–72.9%]), and chronic pain (98.9% [95% CI: 98.3–99.2%]). In contrast, HSD respondents reported a mean of 17 comorbidities, a 17.5-year time to diagnosis, and lower rates of key complications. Triggering events, such as puberty and infections were commonly reported preceding hEDS or HSD symptom onset. Comparison to the All of Us dataset revealed significantly elevated prevalence ratios of neurological, immune, and autonomic diagnoses. Conclusions: This global survey highlights the extensive multisystemic burden and diagnostic delays faced by individuals with hEDS and HSDs. The high prevalence of immune, neurological, gastrointestinal, and autonomic dysfunctions challenges the notion of these conditions as isolated connective tissue disorders. These findings highlight the need for updated diagnostic frameworks and mechanistic studies that explore multifactorial etiologies beyond the connective tissue paradigm.

Cancer is the second most common cause of death in the United States, accounting for 602,350 deaths in 2020. Cancer-related death rates have declined by 27% over the past two decades, partially due to the identification of novel anti-cancer drugs. Despite improvements in cancer treatment, newly approved oncology drugs are associated with increased toxicity risk. These toxicities may be mitigated by pharmacokinetic optimization and reductions in off-target interactions. As such, there is a need for early-stage implementation of pharmacokinetic (PK) prediction tools. Several PK prediction platforms exist, including pkCSM, SuperCypsPred, Pred-hERG, Similarity Ensemble Approach (SEA), and SwissADME. These tools can be used in screening hits, allowing for the selection of compounds were reduced toxicity and/or risk of attrition. In this short commentary, we used PK prediction tools in the optimization of mitogen activated extracellular signal-related kinase kinase 1 (MEK1) inhibitors. In doing so, we identified MEK1 inhibitors with retained activity and optimized predictive PK properties, devoid of hERG inhibition. These data support the use of publicly available PK prediction platforms in early-stage drug discovery to design safer drugs.

Hypermobile Ehlers–Danlos Syndrome (hEDS) is a poorly understood connective tissue disorder that lacks molecular diagnostic markers. This study aimed to identify proteomic signatures associated with hEDS to define underlying pathophysiology and to inform objective diagnostic strategies with therapeutic potential. An unbiased mass spectrometry–based proteomic analysis of serum from female hEDS patients (n = 29) and matched controls (n = 29) was conducted. Differentially abundant proteins were analyzed through pathway enrichment and gene ontology pipelines. Prioritized candidate biomarker proteins were verified in expanded patient and control cohorts via ELISA. Cytokine array profiling was conducted to assess immune signaling patterns. Proteomic analysis revealed 35 differentially expressed proteins in hEDS, with 43% involved in the complement cascade and 80% linked to immune, coagulation, or inflammatory pathways. Pathway analyses confirmed enrichment in complement activation, coagulation, and stress responses. ELISA validation showed significant reductions in C1QA, C3, C8A, C8B, and C9 in hEDS patients, consistent across age and sex. Cytokine profiling revealed alterations in nodal immune cell mediators in hEDS patients, supporting a model of dysregulated inflammatory response. Our findings indicate a systemic immune dysregulation, particularly involving the complement system and profibrotic cytokines, as a common feature in hEDS pathophysiology. These findings challenge the traditional view of hEDS as solely a connective tissue disorder and support a revised paradigm that includes innate immune dysfunction. This immune involvement may contribute to disease pathophysiology and inform the development of biologically based diagnostic tools, enabling earlier diagnosis and guiding future therapeutic strategies.

Intercellular interactions among cardiac cell populations are essential for cardiac morphogenesis, yet the molecular mechanisms orchestrating these events remain incompletely understood. Dachsous1 (Dchs1), an atypical cadherin linked to mitral valve prolapse, is a core planar cell polarity protein whose function in the developing heart has not been fully elucidated. To address this, we generated a Dchs1-HA knock-in mouse model to define its spatial, temporal, and cellular expression patterns. Using immunohistochemistry, western blotting, and single-cell transcriptomics across developmental stages, we demonstrate that cardiac Dchs1 expression is restricted to non-cardiomyocyte lineages. DCHS1 displays dynamic subcellular localization and tissue organization depending on the developmental timepoint, with staining being found in epicardial and endocardial surfaces at earlier embryonic stages and in the compact myocardium in later fetal and neonatal stages. During fetal and neonatal stages, DCHS1-positive non-myocyte, non-endothelial cells form polarized extensions that bridge endothelial and non-myocyte, non-endothelial cells, suggesting direct heterotypic and homotypic interactions. Western blotting revealed evidence of DCHS1 proteolytic cleavage, with intracellular C-terminal fragments. RNA co-expression with its binding partner FAT4 supports a conserved, non-myocyte-specific DCHS1-FAT4 signaling axis. These findings identify DCHS1 as a potential molecular tether that is utilized in intercellular communications during cardiac development, with implications for congenital and acquired heart disease.

Recent evidence demonstrates that mitral valve prolapse (MVP) increases mechanical stress on the subvalvular apparatus and is linked to regional myocardial fibrosis and life-threatening ventricular arrhythmias. However, current surgical guidelines do not account for the extent of myocardial fibrosis or the severity of leaflet involvement, both key features of arrhythmogenic MVP. To address this gap, we conducted histopathological analysis of endomyocardial biopsies from patients with MVP and regionalized myocardial fibrosis (n = 6) who underwent mitral valve repair. Using digital pathology-based quantitative image analysis (QIA), we found that fibrosis in peri-papillary biopsies exhibited a significantly higher Morphometric Composite Score compared with remote biopsies (5.68 ± 0.69 vs. 3.71 ± 0.49, p = 0.042), reflecting larger, more branched, and more assembled collagen fibers, indicative of a mature and persistent fibrotic phenotype. These findings suggest that myocardial scarring in MVP is well-established by the time of surgery and underscore the potential value of earlier surgical intervention to reduce the risk of arrhythmia and preserve post-operative left ventricular function.

Background/Objectives: Dermatosparaxis Ehlers–Danlos syndrome (dEDS) is a rare autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in ADAMTS2, which encodes the primary N-proteinase responsible for fibrillar procollagen processing. Although defective procollagen cleavage is the defining molecular feature of dEDS, how ADAMTS2 deficiency disrupts extracellular matrix (ECM) organization and tissue integrity remains incompletely understood. Here we characterized the structural, molecular, and cellular consequences of a knock-in Adamts2 mouse model harboring a disease-associated variant and assessed its phenotypic and mechanistic resemblance to human dEDS. Methods: We generated Adamts2^Q226* mice carrying a variant analogous to a human dEDS-causing mutation. Skin from homozygous, heterozygous, and control animals was evaluated using histologic, ultrastructural, biochemical, digital pathology, and single-nucleus RNA-sequencing approaches. Pathway enrichment analyses and the computational tool CellChat were used to infer altered molecular programs and changes in intercellular communication. Results: Homozygous knock-in mice exhibited near-complete loss of dermal ADAMTS2 protein expression, impaired type I procollagen processing, disrupted dermal architecture, and irregular hieroglyphic collagen fibrils characteristic of dEDS. Digital pathology demonstrated reduced collagen bulk, diminished assembled and total collagen, increased fine collagen, and loss of mature collagen architecture, with intermediate changes in heterozygous animals. Single-nucleus RNA sequencing identified fibroblasts as the most affected population, with coordinated downregulation of collagen, microfibrillar, and other ECM-associated genes. Pathway analyses implicated altered ECM organization, receptor-linked signaling, cytoskeletal regulation, protein processing, and metabolism, while CellChat inferred widespread reductions in intercellular communication. Conclusions: ADAMTS2 deficiency causes fibroblast-enriched transcriptional remodeling, impaired collagen processing and ECM maturation, and disrupted tissue-wide cellular communication. This model provides a translational platform for studying dEDS pathogenesis and strategies to restore ECM homeostasis.