Ehlers-Danlos Syndromes (EDS) are a group of inherited disorders that affect the body’s connective tissue, which provides support and structure to the skin and other bodily systems. These conditions are caused by genetic changes that disrupt the normal production or processing of collagen, the protein responsible for tissue strength and elasticity. With 13 distinct types recognized in the 2017 International Classification, the diagnostic approach varies significantly depending on the patient’s symptoms and family history. Diagnosis typically involves a combination of clinical evaluation and genetic analysis to determine the specific subtype.
Genetic Testing’s Role in Confirmation
Genetic testing is used to confirm the presence of specific gene mutations that cause the majority of EDS types. Following a physician’s initial clinical suspicion, a blood or saliva sample is collected and analyzed to identify a pathogenic variant in the patient’s DNA. This testing is crucial for pinpointing the exact genetic change responsible for the disorder. Identifying the specific gene mutation confirms the diagnosis and helps distinguish EDS from other heritable connective tissue disorders, such as Marfan or Loeys-Dietz syndromes.
For most types of EDS, a positive genetic test provides definitive molecular confirmation. These tests are typically performed using modern sequencing technologies that analyze a panel of genes associated with various EDS types. A confirmed genetic diagnosis is important for informing personalized medical management and understanding the long-term outlook of the condition.
Specific EDS Types with Definitive Gene Tests
Twelve out of the 13 recognized EDS subtypes have a genetic cause, making genetic testing the standard for diagnosis. Vascular EDS (vEDS), considered one of the most serious types due to the risk of organ and arterial rupture, is caused by mutations in the COL3A1 gene. Classical EDS (cEDS), characterized by skin hyperextensibility and atrophic scarring, is usually linked to mutations in the COL5A1 or COL5A2 genes.
Other rarer subtypes also have specific genetic markers. Kyphoscoliotic EDS (kEDS), which involves severe, progressive scoliosis and eye fragility, is associated with defects in the PLOD1 or FKBP14 genes. Arthrochalasia EDS (aEDS), often presenting with congenital hip dislocation, is caused by mutations in COL1A1 or COL1A2.
These conditions are caused by a single, identifiable mutation. The identification of these pathogenic variants is necessary to meet the diagnostic criteria for these specific EDS types. For these genetically defined types, a clinical diagnosis is considered provisional until molecular testing confirms the gene defect.
The Clinical Diagnosis of Hypermobile EDS
Hypermobile EDS (hEDS) is the most common form of the syndrome, but its definitive genetic cause remains unknown. Consequently, there is currently no specific genetic test to confirm an hEDS diagnosis. Diagnosis is reached through a clinical process based on the 2017 international diagnostic criteria. This involves a physical evaluation to assess for generalized joint hypermobility, often quantified using the Beighton Scale. The criteria also require systemic manifestations, such as velvety skin texture, chronic pain, or recurrent dislocations, and a consistent family history.
hEDS is considered a diagnosis of exclusion, meaning the medical team must first rule out all other genetically defined types of EDS and similar connective tissue disorders. Genetic testing is utilized in the diagnostic workup to exclude other conditions, rather than to confirm hEDS itself. A gene panel is ordered to ensure the patient does not have another genetically-defined form of EDS, particularly those with overlapping symptoms like Classical or Vascular EDS. Once other possibilities have been excluded, and the patient meets all clinical criteria, an hEDS diagnosis can be made.
Interpreting Results and Genetic Counseling
The results of genetic testing for EDS can fall into three categories: positive, negative, or a Variant of Unknown Significance (VUS). A positive result means a known disease-causing mutation was found, confirming the EDS subtype. A negative result means no known pathogenic variants were identified, which may confirm hEDS or suggest a different diagnosis entirely. A VUS is a change in the DNA sequence whose effect on health is not yet clear, making the result inconclusive.
Interpreting these results requires the expertise of a genetic counselor, a healthcare professional specializing in medical genetics. They help patients understand the meaning of the test findings, including the specific inheritance pattern of the identified gene. Genetic counseling is essential for discussing the implications of the diagnosis for family members and future reproductive planning. Understanding the genetic basis, or lack thereof, for an EDS diagnosis is the first step toward comprehensive, multidisciplinary management of the condition.