Massively Parallel Sequencing/ Multiplex Ligation-dependent Probe Amplification
See Related Tests
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. Some affected individuals also have fast-flow vascular anomalies, including arteriovenous malformations (AVMs) or arteriovenous fistulas (AVFs) in the skin, muscle, bone, spine, or brain. Genetic testing can confirm diagnosis of RASA1-related CM-AVM disorder (CM-AVM1) or EPHB4-related CM-AVM disorder (CM-AVM2) in individuals with clinical findings 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, 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, 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)
- Dermal telangiectasias (CM-AVM2)
- Bier spots (CM-AVM2)
Genetics
Genes
EPHB4 and RASA1
Inheritance
- Autosomal dominant
- De novo variants
- ~33% of cases for RASA1
- ~20% of cases for EPHB4
- Somatic mosaicism has been described
Penetrance
Test Interpretation
Genes Tested
- EPHB4 (NM_004444) and RASA1 (NM_002890)
- See Genes Tested table for more information
Sensitivity/Specificity
- Clinical sensitivity is not well established but is estimated at 65%
- EPHB4
- RASA1
-
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- 92% of detectable RASA1 pathogenic variants are sequence variants
- 8% of detectable RASA1 pathogenic variants are large deletions/duplications
-
- Analytical sensitivity
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- For multiplex ligation-dependent probe amplification (MLPA) of RASA1: 99%
- For massively parallel sequencing:
Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
---|---|---|
SNVs |
99.2 |
96.9-99.4 |
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
Deletions 11-44 bp |
99.9 |
87.8-100 |
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
Insertions 11-23 bp |
99.9 |
62.1-100 |
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
Limitations
- A negative result does not exclude a diagnosis of CM-AVM.
- Interpretation of the test result may be impacted if the patient has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of targeted genes
- Regulatory region and deep intronic variants
- Breakpoints of large deletions/duplications
- Large deletions/duplications in EPHB4 gene
- Noncoding transcripts
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Some variants, due to technical limitations in the presence of pseudogenes or repetitive or homologous regions
- Low-level somatic variants
Gene | MIM# | Disorder | Inheritance |
---|---|---|---|
EPHB4 |
600011 |
CM-AVM2 Lymphatic malformation 7 |
AD |
RASA1 |
139150 |
CM-AVM1 |
AD |
AD, autosomal dominant; CM-AVM, capillary malformation-arteriovenous malformation |
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.
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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.
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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.
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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]
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.
Preferred test to detect CM-AVM; assesses for RASA1-associated CM-AVM1 and EPHB4-associated CM-AVM2