Hereditary Hemorrhagic Telangiectasia Panel

Last Literature Review: May 2022 Last Update:

Recommended diagnostic test for individuals with clinical features of HHT

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

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. Overlapping disorders include BMP9/GDF2-related vascular-anomaly syndrome, BMPR2-related disorders, capillary malformation-arteriovenous malformation (CM-AVM), and SMAD4-related juvenile polyposis syndrome (JPS)/HHT. Genetic testing can confirm a diagnosis.

Disease Overview

Symptoms

  • HHT (ACVRL1 and ENG) 
    • 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
  • Related disorders with HHT clinical overlap, including cutaneous AVMs and/or telangiectases 
    • HHT symptoms and juvenile polyps are present with juvenile polyposis syndrome (JPS)/HHT (SMAD4)
    • CM-AVM (RASA1 and EPHB4)
    • BMP9/GDF2-related vascular-anomaly syndrome
    • BMPR2-related disorders

Genetics

Genes

See the Genes Tested table. Additional targeted regions include the 5' untranslated region of ENG, and a region of ACVRL1 intron 9 encompassing the CT-rich variant hotspot region.

Penetrance

Approximately 95% of individuals with HHT will develop symptoms by late adulthood. 

Prevalence

1/5,000 to 1/10,000  

Inheritance

Autosomal dominant for all genes tested

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.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

  • Approximately 97% of individuals meeting consensus clinical diagnostic criteria for HHT will have a causative variant in ACVRL1, ENG, or SMAD4.
    • ACVRL1 and ENG are causative for approximately 96% of HHT.  
      • 90% detectable by sequencing
      • 10% detectable by large deletion/duplication analysis
    • SMAD4 is causative for 1% of HHT.  
    • 3% unknown  
  • BMP9/GDF2 pathogenic variants are detected in <1% of individuals with suspected HHT and no other causative variants. 
  • Approximately 60% of individuals with capillary malformation-arteriovenous malformation (CM-AVM) have detectable pathogenic variants in the EPHB4 and RASA1 genes. 
  • The clinical sensitivity of BMPR2-related disorders in individuals with suspected HHT is unknown.

Analytic Sensitivity

For massively parallel sequencing:

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. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytical 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

One pathogenic variant detected

Confirms a diagnosis; see Genes Tested table for disease association

Negative

No pathogenic variants detected

Reduces risk for HHT and other hereditary conditions tested, but not excluded

Uncertain

Variant of unknown clinical significance detected

It is unknown whether variant is benign or pathogenic

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 (excluding the 5' untranslated region of ENG, and a region of ACVRL1 intron 9 encompassing the CT-rich variant hotspot region)
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Large duplications less than 3 exons in size
    • Single exon deletions/duplications in the following exons:
      • ENG (NM_001114753, NM_000118) 1
    • Noncoding transcripts
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

Genes Tested

Gene Alias Symbol(s) MIM Number Disorder

ACVRL1

ACVRLK1, ORW2, HHT2, ALK1, HHT

601284

HHT, type 2
BMPR2 n/a 600799 BMPR2-related disorders; familial primary pulmonary hypertension with or without HHT

ENG

ORW1, ORW, END, HHT1, CD105

131195

HHT, type 1

EPHB4

HTK, Tyro11

600011

CM-AVM

GDF2

BMP-9, BMP9

605120

 BMP9/GDF2-related vascular-anomaly syndrome

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; n/a, not available

References

Related Information
Hereditary Hemorrhagic Telangiectasia - HHT