Vascular Malformations Panel, Sequencing and Deletion/Duplication

Vascular Malformations Panel, Sequencing and Deletion/Duplication 2007384
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Preferred DNA test to confirm clinical diagnosis of a genetic-related vascular malformation disorder, such as a capillary malformation, arteriovenous malformation, cerebral cavernous malformation, glomuvenous malformation, hereditary hemorrhagic telangiectasia, multiple cutaneous and mucosal venous malformations, pulmonary arterial hypertension, or hereditary lymphedema syndrome, if no single specific diagnosis is strongly suspected.

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.

Disease Overview

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.

Test Description

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.)

Limitations

  • 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:

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

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

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

Genes Tested

Gene MIM Number Disorder Inheritance

ACVRL1

601284

Hereditary hemorrhagic telangiectasia, type 2

AD

AKT1

164730

Proteus syndrome

AD with somatic mosaicism

BMPR2

600799

Primary pulmonary hypertension 1

Pulmonary venoocclusive disease 1, autosomal dominant

AD

CAV1

601047

Primary pulmonary hypertension 3

Partial lipodystrophy, congenital cataracts, and neurodegeneration

Congenital generalized lipodystrophy type 3

AD

CCBE1

612753

Hennekam lymphangiectasia-lymphedema syndrome 1

AR

CCM2

607929

Cerebral cavernous malformations 2

AD

EIF2AK4

609280

Pulmonary venoocclusive disease 2, autosomal recessive

AR

ELMO2

606421

Primary intraosseous vascular malformation

AR

ENG

131195

Hereditary hemorrhagic telangiectasia type 1

AD

EPHB4

600011

Capillary malformation-arteriovenous malformation syndrome

AD

FAT4

612411

Van Maldergem syndrome 2

Hennekam lymphangiectasia-lymphedema syndrome 2

AR

FLT4

136352

Hereditary lymphedema IA

Capillary infantile hemangioma

AD

FOXC2

602402

Lymphedema-distichiasis syndrome

AD

GATA2

137295

Primary lymphedema with myelodysplasia

Emberger syndrome

AD

GDF2 (BMP9)

605120

Hereditary hemorrhagic telangeictasia type 5

AD

GJC2

608803

Hereditary lymphedema IC

AD

GLMN

601749

Glomuvenous malformations

AD

KCNK3

603220

Primary pulmonary hypertension 4

AD

KRIT1

604214

Cerebral cavernous malformations

AD

PDCD10

609118

Cerebral cavernous malformations 3

AD

PIEZO1

611184

Hereditary lymphedema III

AR

PIK3CA

171834

Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP)

Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities (CLOVES)

Capillary malformation of the lower lip, lymphatic malformation of face and neck, asymmetry of face and limbs, and partial/generalized overgrowth (CLAPO)

AD with somatic mosaicism

PTEN

601728

PTEN-related Proteus syndrome

PTEN hamartoma tumor syndrome

AD

RASA1

139150

Capillary malformation-arteriovenous malformation

Parkes Weber syndrome

AD

SMAD4

600993

Juvenile polyposis/hereditray hemorrhagic telangiectasia syndrome

AD

SMAD9

603295

Primary pulmonary hypertension 2

AD

SOX18

601618

Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome

AD

Hypotrichosis-lymphedema-telangiectasia syndrome AR

STAMBP

606247

Microcephaly-capillary malformation syndrome

AR

TEK

600221

Multiple cutaneous and mucosal venous malformations

AD

VEGFC

601528

Hereditary lymphedema ID

AD

AD, autosomal dominant; AR, autosomal recessive
References 
  1. McDonald J, Pyeritz R. Hereditary Hemorrhagic Telangiectasia. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Feb 2017; Accessed: Nov 2018]
  2. 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]
  3. Biesecker L, Sapp J. Proteus Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Jan 2018; Accessed: Nov 2018]
  4. Tournier-Lasserve E. Familial cerebral cavernous malformation. Orpha.net. [Last Update: Mar 2014; Accessed: Nov 2018]
  5. Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007; 30(1): 104-9. PubMed
  6. Williams JB, Hamilton K, Shiller M, Fischer L, Deprisco G, Boland R. Combined juvenile polyposis and hereditary hemorrhagic telangiectasia. Proc (Bayl Univ Med Cent). 2012; 25(4): 360-4. PubMed

Last Update: April 2019