Genetic Screening for Ehlers-Danlos Syndrome (EDS): A Comprehensive Guide

By Brandon Colby, MD, Genomics Specialist
Last Updated: February 27, 2025

What is Ehlers-Danlos Syndrome?

Ehlers-Danlos syndrome (EDS) refers to a group of inherited connective tissue disorders that affect collagen, a protein providing strength and elasticity to tissues including skin, joints, blood vessels, and organs. Faulty collagen caused by genetic variants leads to various EDS symptoms.

Common features include:

Joint hypermobility (flexible joints)
Stretchy skin that bruises easily
Tissue fragility
Chronic pain
Joint instability and recurrent dislocations
Cardiovascular issues (in some types)

Early diagnosis through genetic screening aids proper management and prevents complications.

Types of Ehlers-Danlos Syndrome

There are 13 recognized EDS types, each with distinct genetics and clinical features.

1. Hypermobile EDS (hEDS)

Prevalence: 1 in 3,100 - 5,000
Genes: Unknown (Preliminary research has identified a potential link between the KLK15 gene and hEDS.)
Protein: Unknown
Inheritance: Autosomal Dominant
Features: Joint hypermobility, instability, chronic pain

2. Classical EDS (cEDS)

Prevalence: 1 in 20,000 - 40,000
Genes: COL5A1, COL5A2, COL1A1
Protein: Type V collagen, Type I collagen
Inheritance: Autosomal Dominant
Features: Skin fragility with scars, stretchy velvety skin

3. Vascular EDS (vEDS)

Prevalence: 1 in 100,000 - 200,000
Genes: COL3A1, COL1A1
Protein: Type III collagen, Type I collagen
Inheritance: Autosomal Dominant
Features: Arterial and organ fragility, extensive bruising, pneumothorax

4. Periodontal EDS (pEDS)

Prevalence: <1 in 1,000,000
Genes: C1R, C1S
Protein: C1r, C1s
Inheritance: Autosomal Dominant
Features: Early gum disease, tooth loss, pretibial plaques

Other rare types include Kyphoscoliotic, Spondylodysplastic, Brittle Cornea Syndrome, Arthrochalasia, Musculocontractural, Classical-like, Dermatosparaxis, Myopathic, and Cardiac-valvular EDS.

Genetics and Inheritance of EDS

Genes provide instructions for proteins. Variants (gene differences) can be harmless or pathogenic (harmful), causing faulty proteins leading to disorders like EDS.

Inheritance Patterns

Autosomal Dominant: One pathogenic gene variant causes the condition (50% chance of passing to children; affects both genders equally). Types: hEDS, cEDS, vEDS, pEDS.
Autosomal Recessive: Two pathogenic variants required (both parents must be carriers; each child has a 25% chance). Types: Kyphoscoliotic, Spondylodysplastic, Classical-like.

Genetic Screening for EDS

When to Consider Screening

Symptoms suggesting EDS
Family history
Severe symptoms or complications (arterial rupture, organ fragility)
Definitive diagnosis needed for management
Family planning

Types of Screening

Single Gene Analysis: Specific suspected types (e.g., COL3A1 for vEDS)
Multi-Gene Panel: Multiple genes tested simultaneously for unclear types
Whole Exome Sequencing (WES): Comprehensive, used in complex or unresolved cases

Genetic Screening by EDS Type

Hypermobile EDS (hEDS)

Currently, there is no confirmed genetic cause for hEDS, and diagnosis is based on clinical evaluation of symptoms.

Preliminary research has identified a potential link between the KLK15 gene and hEDS.
Our comprehensive genetic screening includes all genes associated with EDS, including the KLK15 variant.
However, the genetic basis of hEDS remains unclear, and ongoing research is needed to establish any definitive connection.

Classical EDS (cEDS)

90% detectable genetically (COL5A1, COL5A2, rarely COL1A1). Clinical diagnosis still possible if negative.

Vascular EDS (vEDS)

95% detectable genetically (COL3A1, rarely COL1A1). Critical due to life-threatening complications.

Understanding Genetic Screening Results

Positive Result: Confirms diagnosis, guides management, family testing
Negative Result: Condition unclear or undetected, especially hEDS
Variant of Uncertain Significance (VUS): Unknown clinical impact; managed by symptoms, not genetics alone

Benefits of Genetic Screening

Definitive diagnosis for most types
Informed medical management and monitoring
Family planning decisions
Advances research into treatment

Limitations of Genetic Screening

No test for hEDS, Preliminary research has identified a potential link between the KLK15 gene and hEDS.
Genetic complexity (multiple genes)
Testing limitations (variant detection)
Variants of uncertain significance
Cost and insurance coverage challenges

Frequently Asked Questions

Genetic screening advised if symptoms, family history, or severe complications exist.
Consumer tests (23andMe, Ancestry) do not diagnose EDS.
Negative genetic tests don’t rule out EDS (especially hEDS).
Rarely, multiple EDS types may coexist.
Insurance coverage varies; prior authorization may help.

Conclusion

Genetic screening informs diagnosis, management, and family planning for EDS. Consultation with a knowledgeable provider is crucial.

Additional Resources

Sequencing.com’s EDS Screening Test
The Ehlers-Danlos Society
HEDGE Study
Ehlers-Danlos National Foundation
NIH Rare Diseases Information

About The Author

Dr. Brandon Colby MD is a US physician specializing in the personalized prevention of disease through the use of genomic technologies. He’s an expert in genetic testing, genetic analysis, and precision medicine. Dr. Colby is also the Founder of Sequencing.com and the author of Outsmart Your Genes.

Dr. Colby holds an MD from the Mount Sinai School of Medicine, an MBA from Stanford University’s Graduate School of Business, and a degree in Genetics with Honors from the University of Michigan. He is an Affiliate Specialist of the American College of Medical Genetics and Genomics (⁠ACMG), an Associate of the American College of Preventive Medicine (⁠ACPM), and a member of the National Society of Genetic Counselors (⁠NSGC).

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