Hereditary Hemorrhagic Telangiectasia

Recommended test for symptomatic individuals who do not meet clinical criteria for HHT

Recommended test for symptomatic individuals who meet clinical criteria for HHT

Recommended test for symptomatic individuals who meet clinical criteria for HHT

  • Recommended test for a known familial sequence variant previously identified in a family member
  • A copy of the family member’s test results documenting the known familial variant is required

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disorder that leads to abnormal blood vessel formation in the skin, mucous membranes, and often in organs such as the lungs, liver, and brain. Genetic testing can confirm a diagnosis.

Disease Overview

Symptoms

  • Spontaneous and recurring nosebleeds
  • Cutaneous and/or mucosal telangiectases, predominantly on the face, lips, hands, and in oral, nasal, and gastrointestinal mucosa
  • Arteriovenous malformations (AVMs) affecting the lungs, liver, and brain
  • HHT symptoms and juvenile polyps are present with juvenile polyposis  syndrome (JPS)/HHT (SMAD4)

Penetrance

  • Approximately 95% of individuals will develop nosebleeds or telangiectases. 
  • Penetrance is age dependent. 

Prevalence

1/5,000 

Inheritance

Autosomal dominant

Test Description

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

Clinical sensitivity

  • 87% of individuals meeting consensus clinical diagnostic criteria for HHT will have a causative variant in one of the genes tested.
    • Variable for those with symptoms but who do not meet diagnostic criteria
  • ACVRL1 and ENG are causative for ~85% of HHT.    
    • 75% detectable by sequencing
    • 10% detectable by large deletion/duplication analysis
  • SMAD4 is causative for 1-3% of HHT 
  • BMP9/GDF2 mutation are detected in <1% of individuals with no other causative variants. 
  • The clinical sensitivity for EPHB4 is unknown.

Limitations

  • A negative result does not exclude a diagnosis of HHT or overlapping disorders.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the 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 EPHB4
  • 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

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 Alias Symbol(s) MIM Number Disorder

ACVRL1

ACVRLK1, ORW2, HHT2, ALK1, HHT

601284

HHT, type 2

ENG

ORW1, ORW, END, HHT1, CD105

131195

HHT, type 1

EPHB4

HTK, Tyro11

600011

CM-AVM

GDF2

BMP-9, BMP9

605120

HHT, type 5

RASA1

RASA, GAP, CM-AVM, p120GAP, p120RASGAP, p120

139150

CM-AVM, Parkes Weber syndrome

SMAD4

MADH4, DPC4

600993

JPS, JPS/HHT

CM-AVM, capillary malformation-arteriovenous malformation

References