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

Incidence

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

Symptoms/Manifestations

  • 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)

Genetics

Genes

EPHB4 and RASA1

Inheritance

Autosomal dominant

Penetrance

  • EPHB4 – 93% 
  • RASA1 – 90-95%

De novo Variants

~33% of cases for RASA1

Variants

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

Test Interpretation

Sensitivity/Specificity

  • 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%

Limitations

  • 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
References 
  1. Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, Chung W, Dubois J, Lacour J, Martorell L, Mazereeuw-Hautier J, Pyeritz RE, Amor DJ, Bisdorff A, Blei F, Bombei H, Dompmartin A, Brooks D, Dupont J, González-Enseñat MA, Frieden I, Gérard M, Kvarnung M, Hanson-Kahn AK, Hudgins L, Léauté-Labrèze C, McCuaig C, Metry D, Parent P, Paul C, Petit F, Phan A, Quere I, Salhi A, Turner A, Vabres P, Vicente A, Wargon O, Watanabe S, Weibel L, Wilson A, Willing M, Mulliken JB, Boon LM, Vikkula M. Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation. 2017; 136(11): 1037-1048. PubMed
  2. Wooderchak-Donahue W, Stevenson DA, McDonald J, Grimmer F, Gedge F, Bayrak-Toydemir P. RASA1 analysis: clinical and molecular findings in a series of consecutive cases. Eur J Med Genet. 2012; 55(2): 91-5. PubMed
  3. Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, Hammer F, Amor DJ, Irvine AD, Baselga E, Dompmartin A, Syed S, Martin-Santiago A, Ades L, Collins F, Smith J, Sandaradura S, Barrio VR, Burrows PE, Blei F, Cozzolino M, Brunetti-Pierri N, Vicente A, Abramowicz M, Désir J, Vilain C, Chung WK, Wilson A, Gardiner CA, Dwight Y, Lord DJ, Fishman L, Cytrynbaum C, Chamlin S, Ghali F, Gilaberte Y, Joss S, Boente MD, Léauté-Labrèze C, Delrue M, Bayliss S, Martorell L, González-Enseñat M, Mazereeuw-Hautier J, O'Donnell B, Bessis D, Pyeritz RE, Salhi A, Tan OT, Wargon O, Mulliken JB, Vikkula M. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013; 34(12): 1632-41. PubMed
  4. Bayrak-Toydemir P, Stevenson D. RASA1-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Oct 2016; Accessed: Nov 2018]
  5. Wooderchak-Donahue WL, Johnson P, McDonald J, Blei F, Berenstein A, Sorscher M, Mayer J, Scheuerle AE, Lewis T, Grimmer F, Richter GT, Steeves MA, Lin AE, Stevenson DA, Bayrak-Toydemir P. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet. 2018; 26(10): 1521-1536. PubMed
Related Information 
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Last Update: June 2019