Is there a genetic component to Ehlers-Danlos Syndrome (EDS)?

Genetic Components of Ehlers-Danlos Syndrome (EDS)

Yes, Ehlers-Danlos Syndrome (EDS) has a strong genetic component, with 13 of the 14 recognized types having identified genetic causes involving mutations in 20 different genes. 1, 2

Types of EDS and Their Genetic Basis

Genetically Confirmed Types

• Classic EDS:

  • Caused by mutations in COL5A1 and COL5A2 genes, which encode the α1 and α2 chains of type V collagen 3
  • Approximately 50-52% of patients with clinical diagnosis of classic EDS have identifiable mutations in these genes 3, 4
  • Most mutations result in a nonfunctional COL5A1 allele leading to haploinsufficiency of type V collagen 3

• Vascular EDS:

  • Associated with mutations in COL3A1 gene 5
  • Characterized by arterial fragility and risk of dissection 5

• Other EDS Types:

  • Collectively, 13 of 14 recognized EDS types have identified genetic causes 2, 6
  • These involve 21 confirmed genes, most of which encode:
    • Fibrillar collagen types I, III, and V
    • Enzymes that modify or process these proteins
    • Enzymes that modify glycosaminoglycan chains of proteoglycans 2

Hypermobile EDS (hEDS)

• No identified genetic cause yet:
  • The most common type of EDS (80-90% of EDS cases) 5
  • Currently diagnosed through clinical criteria only 1, 6
  • Unlikely to represent a single gene disorder in most affected individuals 6
  • May have a complex genetic basis that remains to be elucidated

Inheritance Patterns

• Autosomal dominant: Many EDS types, including classic EDS, follow this pattern 5, 7
• Autosomal recessive: Some rarer types of EDS follow this pattern 7
• Familial aggregation: Family history is an important diagnostic consideration 1

Clinical Implications of Genetic Testing

• Diagnostic value:

  • Genetic testing is indicated when clinical features suggest a monogenic EDS type 6
  • SDS-PAGE analysis of fibroblast cultures has poor sensitivity (only 2/48 cases detected) 4
  • More advanced genetic testing methods have improved detection rates

• Genotype-phenotype correlations:

  • Significant inter- and intrafamilial phenotypic variability exists 3
  • No clear genotype-phenotype correlations have been established for classic EDS 3

Associated Conditions with Genetic Overlap

• Postural Orthostatic Tachycardia Syndrome (POTS) and Mast Cell Activation Syndrome (MCAS) frequently co-occur with hEDS 5, 1
• Cardiovascular manifestations: Including aortic aneurysms and dissections, particularly in vascular EDS 5

Clinical Evaluation Approach

• Comprehensive clinical assessment:

  • Joint hypermobility using Beighton scale (score ≥5 indicates hypermobility)
  • Skin examination for hyperextensibility, fragility, poor wound healing
  • Family history
  • Targeted genetic testing based on suspected EDS subtype 1

• Genetic testing strategy:

  • For classic EDS: COL5A1 and COL5A2 sequencing
  • For vascular EDS: COL3A1 sequencing
  • For other suspected types: gene panels based on clinical presentation 6

The genetic understanding of EDS continues to evolve, with ongoing research likely to identify additional genetic causes, particularly for hEDS. This will improve diagnostic accuracy and potentially lead to more targeted treatments in the future.