Vascular Malformations Panel, Sequencing and Deletion/Duplication

Vascular malformation syndromes are caused by defects of blood vessels, which can affect multiple vessel types (venous, arterial, capillary, or combined). If no single specific diagnosis is strongly suspected, a DNA test can confirm clinical diagnosis of a genetic-related vascular malformation disorder.

Findings

• Hemorrhage and/or epistaxis
• Localized pain and/or lymphedema
• Destruction/deformation of surrounding tissue
• Localized intravascular coagulopathy (LIC)
• Stroke or congestive heart failure
• Pulmonary arterial hypertension (PAH)

Etiology

Pathogenic variants in vascular malformation genes lead to defects of blood vessels, causing fast-flow or slow-flow lesions, shunting, swelling, or skin findings. For some disorders, this may lead to potentially life-threatening hemorrhage, stroke, or heart failure.

Prevalence

• Hereditary hemorrhagic telangiectasia (HHT) – 1 in 10,000
• Familial cerebral cavernous malformation (CCM) – 1 in 2,000 to 10,000
• RASA1-related disorders (CM-AVM, Parkes Weber) – approximately 1 in 100,000
• Pulmonary Arterial Hypertension (PAH) – 1-2/100,000
• PTEN-related Proteus syndrome (PS)/Proteus-like syndrome (PLS) – estimated <1 in 1,000,000
• Juvenile polyposis/hereditary hemorrhagic telangiectasia (JP/HHT) syndrome – approximately 1 in 100,000

Inheritance

• Autosomal recessive for CCBE1, EIF2AK4, ELMO2, FAT4, PIEZO1, and STAMBP
• Autosomal dominant and autosomal recessive for SOX18
• Autosomal dominant with somatic mosaicism for AKT1 and PIK3CA
• Autosomal dominant for all other genes

Genotype-Phenotype Correlation

• Vascular malformation syndromes are typically categorized according to vessel type affected and fast- vs. slow-flow lesions.
• Most vascular malformations are sporadic.
• Inherited forms are characterized by multiple lesions, which are often smaller and less often congenital than their sporadic counterparts.
• Penetrance is often age-related and variable.

See the Genes Tested table for the coding regions and intron-exon boundaries of 30 genes, the 5' untranslated region of ENG, and a region of ACVRL1 intron 9 encompassing the CT-rich variant hotspot region.

Clinical Sensitivity

Variable and dependent upon specific disorder

Testing Strategy

If an individual meets clinical criteria for a specific disorder or if a specific diagnosis is suspected, consider more targeted gene testing first. (See Related Tests.)

• A negative result does not exclude a heritable form of a vascular malformation disorder.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this individual has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of the targeted genes
  • Regulatory region variants and deep intronic variants
  • Breakpoints of large deletions/duplications
  • Deletions/duplications in AKT1, EIF2AK4, ELMO2, EPHB4, FAT4, GATA2, PIEZO1, PIK3CA, SMAD9, SOX18, STAMBP, VEGFC
  • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • PIK3CA (NM_006218) 10,11,12,13,14
    • SOX18 (NM_018419) 1
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Deletions/duplications less than 1kb in the targeted genes by array
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants
  • Single exon deletions/duplications in the following exons:
    • FLT4 (NM_002020) 30; FLT4 (NM_182925) 20, 22; GLMN (NM_053274) 11; PTEN (NM_000314) 8, 9; PTEN (NM_001304717) 1; TEK (NM_000459) 1

Analytical Sensitivity

For massively parallel sequencing: