Capillary Malformation-Arteriovenous Malformation

Capillary Malformation-Arteriovenous Malformation (EPHB4 and RASA1) Sequencing, and (RASA1) Deletion/Duplication 3001132
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Most comprehensive DNA test for CM-AVM (CM-AVM1 and CM-AVM2)

RASA1-Related Disorders (RASA1) Sequencing and Deletion/Duplication 2007852
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Preferred DNA test for RASA1-related disorders (CM-AVM1) only

RASA1-Related Disorders (RASA1) Sequencing 2002730
Method: Polymerase Chain Reaction/Sequencing

DNA test for RASA1-related disorders (CM-AVM1) only

DNA test for EPHB4-related CM-AVM (CM-AVM2) only​

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Vascular Malformations Panel, Sequencing and Deletion/Duplication 2007384
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Preferred DNA test to confirm clinical diagnosis of a heritable vascular malformation disorder

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a pathogenic familial variant identifiable by sequencing is known

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a disorder of the vascular system characterized by enlarged capillaries that appear as small, round dots on the skin. Genetic testing can confirm diagnosis of RASA1-related CM-AVM disorder (CM-AVM1), or an EPHB4-related CM-AVM disorder (CM-AVM2), in individuals with symptoms suggestive of CM-AVM.

Disease Overview


  • ~1/20,000 for CM-AVM1
  • ~1/12,000 for CM-AVM2  


  • Multifocal CMs; commonly localized on skin of the trunk, limbs, or face
    • Fast flow lesions
      • AVM, arteriovenous fistula (AVF), and vein of Galen malformation located in the brain, spine, skin, or muscle may cause life-threatening complications
        • Bleeding
        • Congestive heart failure
        • Neurological consequences
      • In Parkes Weber Syndrome (PKWS), diffuse subcutaneous/intramuscular micro AVFs associated with hypertrophy of the involved extremity
  • Lymphatic abnormalities
  • Recurrent epistaxis (CM-AVM2, but uncommon)
  • Telangiectasias – dermal (CM-AVM2, but less common than CMs)





Autosomal dominant


  • EPHB4 – 93% 
  • RASA1 – 90-95%

De novo Variants

~33% of cases for RASA1


  • 92% of RASA1 pathogenic variants detectable by sequencing
  • 8% of RASA1 pathogenic variants detectable by deletion/duplication analysis

Test Interpretation


  • Clinical sensitivity for CM-AVM – not well established and varies based on clinical manifestations; estimates based on available publications
    • EPHB4
      • Sequencing – at least 15%
        • Detected in 15% of individuals with sporadic or familial CMs with or without fast-flow lesions 
      • Deletion/duplication – unknown
    • RASA1
      • Sequencing – ~30-70%
        • Detected in 30% of consecutive cases with or without CMs,  with higher detection rate in individuals with multifocal CMs
        • Detected in 70% of individuals with multifocal CMs with or without fast-flow lesions 
      • Deletion/duplication – ~8% 
  • Analytical sensitivity/specificity for sequencing of EPHB4 and RASA1, and MLPA of RASA1 – 99%


  • Diagnostic errors can occur due to rare sequence variations
  • Not determined or evaluated
    • Large deletions/duplications in EPHB4
    • Regulatory region and deep intronic variants
    • Breakpoints for large deletions/duplications identified in RASA1
    • Variants in genes other than EPHB4 and RASA1
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  4. Bayrak-Toydemir P, Stevenson D. RASA1-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Oct 2016; Accessed: Jul 2019]
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Last Update: June 2019