Capillary Malformation-Arteriovenous Malformation

Use to detect CM-AVM. If vascular symptoms are expanded beyond CM-AVM, consider ordering the Vascular Malformations Panel, Sequencing and Deletion/Duplication.

  • Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
  • To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor at 800-242-2787.

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. These lesions may cause life-threatening complications such as bleeding, congestive heart failure, or neurological consequences. Additional manifestations include lymphatic abnormalities, recurrent epistaxis (CM-AVM2), dermal telangiectasias (CM-AVM2), and bier spots (CM-AVM2). 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

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

Genetics

Genes

  • EPHB4 (NM_004444) and RASA1 (NM_002890)
  • See Genes Tested table for more information

Inheritance

  • Autosomal dominant
  • De novo variants
    • Approximately 33% of cases for RASA1
    • Approximately 20% of cases for EPHB4
  • Somatic mosaicism has been described

Penetrance

  • EPHB4: 93% 
  • RASA1: 90-99%

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

Clinical sensitivity is not well established but is estimated at 60% 

  • EPHB4
    • An estimated 10% of CM-AVM is attributed to EPHB4
      • Detected in 15% of individuals with sporadic or familial CMs with or without fast-flow lesions 
    • To date, all described pathogenic variants are detectable by sequencing
    • Clinical sensitivity of deletion/duplication analysis is unknown
  • RASA1
    • An estimated 50% of CM-AVM attributed to RASA1
    • Detected in approximately 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 
    • 92% of detectable RASA1 pathogenic variants are sequence variants and 8% are large deletions/duplications

Analytic Sensitivity

Variant Class Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region Analytic Specificity (NPA)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]

>99.9

Exon-levelc duplications

83.3 (56.4-96.4) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Results

Result Variant(s) Detected Clinical Significance

Positive

Pathogenic EPHB4 or RASA1 variant detected

Confirms diagnosis of CM-AVM in a symptomatic individual

Negative

No known pathogenic EPHB4 or RASA1 variant detected

Reduces possibility of, but does not exclude, a diagnosis of CM-AVM

Inconclusive

Variant of uncertain clinical significance detected in EPHB4 or RASA1

Unclear if variant is disease causing or benign

Limitations

  • A negative result does not exclude a diagnosis of CM-AVM.
  • Diagnostic errors can occur due to rare sequence variations.
  • 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
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by MPS
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Some variants, due to technical limitations in the presence of pseudogenes or repetitive or homologous regions
    • Low-level somatic variants

Genes Tested

Gene MIM# Disorder Inheritance
EPHB4 600011

CM-AVM2

Lymphatic malformation 7

 AD
RASA1 139150 CM-AVM1 AD
AD, autosomal dominant

References

Additional Resources
Related Information
Hereditary Hemorrhagic Telangiectasia - HHT