Hereditary Hemorrhagic Telangiectasia (HHT) Testing

Hereditary hemorrhagic telangiectasia (HHT) is an inherited condition causing abnormalities in the blood vessels.  Frequent nosebleeds, characteristic skin findings, and blood vessel malformations are common.  Establishing a genetic diagnosis not only guides management for patients, but also identifies family members that may benefit from life-saving screening and treatment.   

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Hereditary hemorrhagic telangiectasia (HHT) is an inherited condition causing abnormalities in the blood vessels.  Frequent nosebleeds, characteristic skin findings, and blood vessel malformations are common.  Establishing a genetic diagnosis not only guides management for patients, but also identifies family members that may benefit from life-saving screening and treatment.   

Ambry offers tiered, comprehensive next generation sequencing (NGS) panels of the 5 most common genes associated with HHT in order to provide accurate results for patients and their families and help guide their care and management. 

Disease Name 
Hereditary hemorrhagic telangiectasia (HHT)
Osler-Weber-Rendu syndrome
Disease Information 

Hereditary hemorrhagic telangiectasia (HHT) causes malformations of the blood vessels.  It is thought to occur in about 1 in 10,000 people in the United States, but this is likely an underestimate due to those going undiagnosed.1 Normally, blood pumps from arteries to small capillaries in order to provide oxygen to the tissues.  After this, blood enters the veins to return to the lungs.  However, in people with HHT, direct connections can form between the arteries and the veins, without intervening capillaries.1   These connections, called arteriovenous malformations (AVMs), can range in size and location.  Small AVMs, called telangiectases, are commonly found on the lips, tongue, face, and fingers, as well as the mucous membranes of the nose, mouth, and gastrointestinal tract.1  These telangiectases often rupture and bleed after slight trauma, and can cause frequent nosebleeds (epistaxis), and gastrointestinal bleeding.2

Large AVMs (ranging from a few millimeters to a few centimeters in diameter) can occur in various organs, including the liver, lungs, and brain.  If brain AVMs occur they are usually seen at birth, while AVMs within the lungs and liver may develop over time.1  Complications from AVMs (like bleeding or cardiac shunting) can be catastrophic, and the stress placed on the heart can lead to cardiac failure.2

HHT shows age-related penetrance, meaning that a person is more likely to express symptoms as they get older.  About half of people with HHT have frequent nosebleeds by age ten years, but 80-90% will have them by age 21 years; over 95% of people will develop them in their lifetime.3  Clinical diagnosis is made based on the presence of three of the four criteria: 1) recurrent nosebleeds (epistaxis); 2) telangiectases on the face, mouth, or gastrointestinal tract; 3) AVMs within organs; and 4) a family history of these.1-4  Continuously screening family members at risk of having inherited this condition is costly, stressful and difficult.5  The screening must be continued until a diagnosis is confirmed, or the individual reaches an age where the clinician can be confident that features will not develop.  However, because of the age-related penetrance, no clear guidelines have been established as to the age when a person is no longer considered to be at risk of having HHT.5 Studies have demonstrated cost-effectiveness of genetic testing for individuals at risk for HHT, as compared to the cost of repeated long-term screening.5 

Genetic testing can be used to confirm a diagnosis and identify family members at risk, allowing screening for AVMs.4  In addition, there is evidence that the type of mutation a person has can predict the likelihood of developing AVMs in particular locations.1-4  Genetic testing in children can be valuable, as it can direct these screening methods, leading to early detection and treatment of potentially life-threatening AVMs.4

Mutations in many genes have been associated with HHT, and are inherited in an autosomal dominant pattern.2  The most common genes associated are ENG and ACVRL1, in which mutations are found in about 85-95.7% of clinically affected individuals (depending on how strictly the diagnostic criteria were used).  Mutations in SMAD4 are found in about 1.4% of those with a clinical diagnosis.3 Other genes, GDF2 and RASA1, are seen in smaller proportions of HHT patients.  Deletions and duplications within these genes have also been reported.3

Ambry’s HHT testing consists of tiered next generation sequencing (NGS) panels, with deletion/duplication analysis included for each gene.  We offer options to meet your clinical needs:

  • HHTFirst includes analysis of the most common genes associated with HHT: ACVRL1, ENG, SMAD4
  • HHTNext is the most comprehensive test. It includes the above and analysis of GDF2 and RASA1

A reflex option (HHTReflex), GDF2 and RASA1 standalone analyses, and Specific Site Analysis of mutations identified previously in a family member, are also available.

Testing Benefits & Indication 

Genetic testing is useful for diagnostic confirmation and testing of at-risk asymptomatic family members.  Testing can help avoid repeated costly screenings (including reducing exposure to radiation)5 and help guide recommendations for surveillance and treatment.4  Genetic testing may be considered for any of the following:

  • Confirming a diagnosis in people with a clinical presentation of HHT
  • People meeting some of the diagnostic criteria for HHT 
  • At-risk family members, including children 
Test Description 

HHTFirst includes 3 genes most commonly associated with HHT: ACVRL1, ENG, and SMAD4. HHTNext includes these genes and 2 additional genes: GDF2 and RASA1.  Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, and is followed by polymerase chain reaction (PCR) and NGS. Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Suspect variant calls are verified by Sanger sequencing.  This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis for available genes is performed utilizing a targeted chromosomal microarray.

Mutation Detection Rate 

85-98% of patients with a clinical presentation of HHT have a detectable mutation on these panels, depending on how strictly the diagnostic criteria are used (clinical sensitivity).3 Ambry's HHT testing can detect >99.9% of described mutations in included genes, when present (analytic sensitivity)

 

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TEST NAME TURNAROUND TIME
8673 HHTFirst
(ACVRL1, ENG, SMAD4)  Gene Sequence Analysis and Del/Dup
14-21 days
8672 HHTNext
(ACVRL1, ENG, SMAD4, GDF2, RASA1) Gene Sequence Analysis and Del/Dup
14-21 days
8671 HHTReflex
(ACVRL1, ENG, SMAD4) Gene Sequence Analysis and Del/Dup ;
reflex to (GDF2, RASA1) Gene Sequence Analysisand Del/Dup
14-28 days
8674 GDF2 and RASA1 standalone Gene Sequence Analysisand Del/Dup 14-21 days


Del/Dup: deletion/duplication analysis

Specialty 
Genes 
ACVRL1
ENG
SMAD4
GDF2
RASA1
References 
  1. McDonald J, et al.  Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011 Jul;13(7):607-16. 
  2. McDonald J and Pyeritz RE. Hereditary Hemorrhagic Telangiectasia. GeneReviews®. Initial posting 2000, updated 2014. Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2014.  
  3. McDonald J, et al. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015 Jan 26;6:1. 
  4. Al-Saleh A, et al. Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia. Eur Respir J. 2009 Oct;34(4):875-81. 
  5. Bernhardt BA, et al. Cost savings through molecular diagnosis for hereditary hemorrhagic telangiectasia. Genet Med. 2012 Jun;14(6):604-10.