Heritability, Genetics, and Counseling in hEDS
Hypermobile Ehlers-Danlos syndrome (hEDS) is widely recognized as a heritable connective tissue disorder, but it remains unique among EDS subtypes in that the genetic cause has not yet been identified. As a result, clinical diagnosis relies on physical criteria rather than a genetic test. This absence of molecular confirmation can lead to confusion, delayed diagnosis, and emotional distress for individuals and families. While hEDS tends to run in families, there are also cases where no one else appears to be affected. Ongoing research is beginning to reveal the likely complexity of its genetic basis, and studies are underway to better understand its patterns of inheritance, clinical variability, and future diagnostic possibilities.
Inheritance Pattern and Family History
Evidence from clinical and population studies supports an autosomal dominant inheritance pattern in most individuals with hEDS. This means that one copy of the altered gene from either parent is sufficient to pass on the condition. On average, each child of an affected individual has a 50% chance of inheriting the condition. However, this figure is based on observation rather than molecular testing, as no definitive gene for hEDS has been identified.
In most families, at least one parent is retrospectively found to have signs of hEDS, such as joint hypermobility, skin elasticity, easy bruising, or musculoskeletal pain. In some cases, these features are mild or were never previously diagnosed, especially in older generations. This phenomenon reflects what researchers describe as variable expressivity (symptoms that differ in severity among individuals) and incomplete penetrance (not everyone who inherits the genetic predisposition shows symptoms).
Despite the dominant inheritance pattern, sporadic cases of hEDS also occur. These may result from de novo mutations—genetic changes that arise spontaneously in the affected individual rather than being inherited from a parent. While the exact rate is unknown, such cases appear to be uncommon. One study of patients evaluated for hEDS found that over 90% had an affected parent or relative, while fewer than 10% had no known family history, suggesting that inherited cases remain the most common.
Although hEDS belongs to the broader group of Ehlers-Danlos syndromes, it is genetically distinct from other EDS subtypes, such as classical (cEDS) or vascular (vEDS) EDS, which have clearly defined mutations in collagen or connective tissue-related genes. There is no evidence that people with hEDS or their relatives are at increased risk for other EDS subtypes, unless a misdiagnosis has occurred. However, hypermobility spectrum disorder (HSD) is often seen in families with hEDS and may represent a milder or incomplete expression of the same underlying genetic predisposition. This familial clustering of hEDS and HSD supports the hypothesis that they lie along a shared heritable spectrum, even though HSD is not officially classified as a subtype of EDS. At present, both hEDS and HSD remain clinical diagnoses with no definitive genetic marker.
Why There Is No Genetic Test
Although hEDS clearly runs in families, efforts to identify a single causative gene have not been successful. Studies using whole exome sequencing (a method that examines the protein-coding regions of all genes) and gene panels (targeted testing of multiple known disease-related genes) have not revealed a consistent pattern of pathogenic mutations. In most people with hEDS, these tests fail to find a known genetic cause, even when symptoms are significant.
Some researchers have proposed candidate genes, such as TNXB (Tenascin-X) and LZTS1, but these account for only a small fraction of cases, and their role remains uncertain. Unlike other types of EDS, which involve identifiable mutations in collagen-related genes, hEDS likely involves polygenic inheritance (multiple genes contributing small effects) or multifactorial inheritance (a combination of genetic and environmental factors). This complexity has made gene discovery more challenging.
Implications for Genetic Counseling
In the absence of a known gene, genetic counseling for hEDS focuses on empirical risk, clinical features, and family history rather than test results. Counselors typically inform families that hEDS appears to be inherited in an autosomal dominant pattern with variable expressivity and incomplete penetrance. This means that a child of an affected parent has an estimated 50% chance of inheriting the condition, but the severity and presentation may differ greatly, even within the same family.
Counseling must also address the limitations of current testing. Because there is no gene test for hEDS, predictive testing (testing a healthy person to see if they will develop a condition) is not available. In children, especially those who are asymptomatic or only mildly affected, diagnosis is often deferred until adolescence or early adulthood unless symptoms are clearly disabling. This is partly because joint hypermobility is common and often normal in younger children, making it difficult to distinguish from a heritable disorder.
In reproductive counseling, prospective parents with hEDS may be informed that prenatal testing and preimplantation genetic diagnosis are not currently available for hEDS, due to the absence of a defined gene. Counseling instead emphasizes education about the nature of the condition, expected variability, and available support.
The Psychological and Social Impact of Diagnostic Uncertainty
Many people with hEDS experience years of symptoms before receiving a diagnosis. This delay can be distressing and is often compounded by medical skepticism, particularly in the absence of a clear laboratory or genetic finding. The absence of a molecular test can contribute to diagnostic insecurity, with some healthcare providers questioning the legitimacy of the diagnosis or attributing symptoms to psychological causes.
Studies show that individuals with hEDS often feel misunderstood by healthcare providers, especially in primary care settings. This sense of invalidation is associated with increased rates of anxiety, depression, and social isolation, and can undermine confidence in medical care. These effects are particularly strong in pediatric and adolescent populations, where diagnostic criteria are harder to apply and symptoms may overlap with normal developmental traits.
Clinical Challenges for Healthcare Providers
For clinicians, the absence of a molecular test means that diagnosis must rely on clinical criteria, physical examination, and exclusion of other conditions. This can be especially challenging in children, older adults, or individuals with subtle or overlapping symptoms. In many cases, genetic testing is still used—but only to rule out other heritable connective tissue disorders such as classical EDS, vascular EDS, Marfan syndrome, or Loeys-Dietz syndrome, all of which do have identifiable genetic causes.
The lack of a genetic test can also limit access to care. Some healthcare systems or insurance plans require a confirmed genetic diagnosis before approving referrals or coverage for services such as physical therapy, psychological support, or multidisciplinary care.
Research and the Future of Diagnosis
Major research efforts are underway to identify the genetic underpinnings of hEDS. These include:
The HEDGE study (Hypermobile Ehlers-Danlos Genetic Evaluation), an international effort to analyze large cohorts of rigorously diagnosed patients.
Genomic studies like the 100,000 Genomes Project, which include people with undiagnosed rare diseases, including connective tissue disorders.
Studies of proteomics (the study of proteins in tissues or blood), which have found potential markers in the blood of people with hEDS that differ from other EDS types or healthy controls.
In 2025, one such study identified distinctive fragments of fibronectin and type I collagen in blood samples from people with hEDS and hypermobility spectrum disorders (HSD). These early results suggest that a blood-based biomarker test may eventually become available, though it is not yet ready for clinical use.
Expected Impact of Gene Discovery
If the causative gene—or combination of genes—for hEDS is discovered, it would significantly change clinical practice. A genetic test would:
Allow objective confirmation of diagnosis, reducing uncertainty and stigma.
Improve access to specialists and insurance-covered services.
Enable carrier testing and presymptomatic counseling for family members.
Support research into disease mechanisms and potential treatments.
Until that discovery occurs, the best approach remains a combination of clinical assessment, family history, coordinated symptom management, and psychosocial support.
Summary
Hypermobile Ehlers-Danlos syndrome is a heritable disorder that is believed to follow an autosomal dominant inheritance pattern, with high but incomplete penetrance and variable severity across individuals. Most people diagnosed with hEDS have at least one affected family member, although some cases appear sporadic, possibly due to new genetic mutations or undetected mild presentations in relatives. Despite strong evidence of heritability, the causative gene or genes have not yet been identified. This lack of a molecular marker complicates diagnosis, counseling, reproductive planning, and access to care. It also contributes to widespread experiences of dismissal and psychological burden among individuals with hEDS. Research is ongoing, and the discovery of genetic markers or blood-based diagnostic tools would represent a major advancement, improving accuracy, legitimacy, and support. Until then, diagnosis and management rely on clinical criteria and multidisciplinary care, underscoring the need for better provider education and comprehensive patient support.
