What is the role of genetic testing in diagnosing Ehlers-Danlos syndrome?

Genetic Testing for Ehlers-Danlos Syndrome

Genetic testing plays a critical diagnostic role for most EDS subtypes except hypermobile EDS (hEDS), where diagnosis remains purely clinical and genetic testing is not recommended. 1, 2

When to Order Genetic Testing

Vascular EDS (Type IV) - URGENT Testing Required

• COL3A1 gene mutation testing should be ordered immediately when vascular EDS is suspected due to life-threatening risk of arterial or organ rupture 1, 3
• Clinical features prompting urgent testing include: thin translucent skin with visible veins, characteristic facial features (thin nose, thin upper lip, small earlobes, prominent eyes), easy bruising, and family history of sudden death or arterial rupture 3
• This is the only EDS subtype where genetic confirmation is both possible and medically urgent 1

Classical EDS (Types I and II)

• COL5A1 or COL5A2 gene mutation testing provides molecular confirmation when clinical features include skin hyperextensibility, atrophic scarring, and joint hypermobility 1
• Genetic testing confirmed diagnosis in 75% of children meeting clinical criteria in one study 4

Other Rare EDS Subtypes

• Genetic testing is indicated when clinical features suggest one of the 12 monogenic EDS subtypes (excluding hEDS) 2
• Multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes is the most efficient approach when EDS is suspected but subtype is unclear 1

When NOT to Order Genetic Testing

Hypermobile EDS (hEDS)

• Genetic testing should NOT be routinely ordered for hEDS, as no causative genes have been identified 1, 2
• hEDS represents 80-90% of all EDS cases and diagnosis is purely clinical using the 2017 criteria 1
• Diagnosis requires: (1) Beighton score ≥5, (2) musculoskeletal/systemic manifestations of connective tissue disorder, and (3) exclusion of alternative diagnoses 5

Critical Pre-Testing Workup

Before ordering genetic testing, complete these essential steps:

Laboratory Studies

• Baseline serum tryptase level (elevated in myeloproliferative variants with arteriopathy) 1, 3
• Vitamin B12 level (characteristically elevated in myeloproliferative variants) 1, 3
• Complete blood count with differential (evaluate for cytopenias or eosinophilia) 1
• Comprehensive metabolic panel including liver and renal function 1

Imaging Studies

• Echocardiogram to evaluate for aortic root dilation (occurs in 25-33% of classic and hypermobile EDS) 6, 1
• MR angiography of head, neck, thorax, abdomen, and pelvis when vascular EDS or Loeys-Dietz syndrome is suspected to assess arterial tortuosity and aneurysms 6, 1, 3

Clinical Assessment

• Beighton score for joint hypermobility (≥5 required for hEDS diagnosis) 6, 1
• Skin assessment for hyperextensibility, fragility, and atrophic scarring 6, 1
• Dilated eye examination to exclude ectopia lentis (seen in Marfan syndrome, not EDS) 6, 1
• Three-generation family history for autosomal dominant inheritance pattern 6, 1

Genetic Testing Strategy

First-Line Testing

• For suspected vascular EDS: COL3A1 gene sequencing immediately 1, 3
• For suspected classical EDS: COL5A1/COL5A2 gene sequencing 1
• For unclear EDS subtype: comprehensive EDS multi-gene panel 1, 4

When Panel Testing is Negative

• Consider whole exome sequencing (WES) if clinical suspicion remains high for a monogenic EDS subtype (not hEDS) 7, 2
• Do NOT order WES or whole genome sequencing for suspected hEDS 1
• Recent research found that 26.4% of patients meeting hEDS clinical criteria had alternative genetic diagnoses identified through comprehensive testing, emphasizing the importance of excluding other conditions 5

Critical Pitfalls to Avoid

Diagnostic Errors

• Failure to recognize vascular EDS carries significant mortality risk - arterial or organ rupture can occur at any age 1
• Performing invasive diagnostic procedures in undiagnosed vascular EDS patients can lead to fatal complications due to tissue fragility 1
• Ordering genetic testing for hEDS wastes resources and delays appropriate clinical management 1, 2

Testing Interpretation

• Genetic testing confirmed only 83% of patients meeting clinical criteria for monogenic EDS subtypes, meaning clinical diagnosis remains paramount 4
• Variants of uncertain significance (VUS) are common and require family segregation studies for reclassification 7
• Genetic heterogeneity means each family typically has its own specific mutation, making systematic screening impractical without clinical guidance 6

Mandatory Genetic Counseling

Formal genetic counseling must be provided before mutation screening due to complex financial, insurance, familial, and social implications 1, 3

Key counseling points include:

• Autosomal dominant inheritance with 50% transmission risk to offspring 1, 3
• Lifelong surveillance strategies including annual imaging for vascular subtypes 3
• Pregnancy planning considerations (high maternal mortality risk in vascular EDS from uterine and arterial rupture) 3
• Surgical risk stratification due to tissue fragility 3
• Family screening implications 3

When to Refer to Medical Genetics

Refer to a medical geneticist when:

• Clinical features suggest any EDS subtype 1
• Family history shows autosomal dominant inheritance of connective tissue features 1
• Arteriopathy or vascular complications are suspected 1
• Initial genetic testing yields VUS requiring interpretation 7
• Patient meets some but not all criteria for hEDS and alternative diagnoses need exclusion 5

Medical geneticists are the primary specialists who diagnose and classify EDS, as they have expertise in evaluating inherited connective tissue disorders and coordinating appropriate genetic testing 1