FeedbackPolymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Preferred DNA test for RASA1-related disorders (CM-AVM1) only
Polymerase Chain Reaction/Sequencing
DNA test for EPHB4-related CM-AVM (CM-AVM2) only
Related Tests
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Most comprehensive test to determine the cause of a telangiectasia/AVM disorder
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Preferred DNA test to confirm clinical diagnosis of a heritable vascular malformation disorder
Polymerase Chain Reaction/Sequencing
Useful when a pathogenic familial variant identifiable by sequencing is known
Capillary malformation-arteriovenous malformation (CM-AVM) syndrome 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 a 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
- AVM, arteriovenous fistula (AVF), and vein of Galen malformation located in the brain, spine, skin, or muscle may cause life-threatening complications
- Fast flow lesions
- 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
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 is not well established and varies based on clinical manifestations; estimates based on available publications
- EPHB4
- RASA1
- 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
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28687708
Amyere M, Revencu N, Helaers R, et al. 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 -
22200646
Wooderchak-Donahue W, Stevenson DA, McDonald J , et al. RASA1 analysis: clinical and molecular findings in a series of consecutive cases. Eur J Med Genet. 2012;55(2):91-95.
PubMed -
24038909
Revencu N, Boon LM, Mendola A, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34(12):1632-1641.
PubMed -
GeneReviews - Capillary Malformation-Arteriovenous Malformation Syndrome
Bayrak-Toydemir P, Stevenson D. Capillary malformation-arteriovenous malformation syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last update: Sep 2019; Accessed: Nov 2020]
Online
29891884
Wooderchak-Donahue WL, Johnson P, McDonald J, et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet. 2018;26(10):1521-1536.
Most comprehensive DNA test for CM-AVM (CM-AVM1 and CM-AVM2)