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Test ID: HHTGP Hereditary Hemorrhagic Telangiectasia Gene Panel, Varies

Advisory Information

Targeted testing for familial variants (also called site-specific or known mutation testing) is available for the genes on this panel. See:

-KVAR1 / Known Variant Analysis-1 Variant, Varies

-KVAR2 / Known Variant Analysis-2 Variants, Varies

-KVAR3 / Known Variant Analysis-3+ Variants, Varies


Call 800-533-1710 to confirm the appropriate test for targeted testing.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

Necessary Information

1. Hereditary Hemorrhagic Telangiectasia (HHT) Gene Testing Patient Information is required, see Special Instructions. Testing may proceed without the patient information however it aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Include physician name and phone number with specimen.

Specimen Required

Submit only 1 of the following specimens:


Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (Preferred)/Refrigerated


Specimen Type: DNA

Container/Tube: 2 mL screw top tube

Specimen Volume: 100 mcL (microliters)

Collection Instructions:

1. The preferred volume is 100 mcL at a concentration of 250 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated


1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. If not ordering electronically, complete, print, and send a Cardiovascular Test Request Form (T724) with the specimen.

Useful For

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of hereditary hemorrhagic telangiectasia (HHT) or a related disorder


Second-tier testing for patients in whom previous targeted gene variant analyses for specific HHT genes were negative


Establishing a diagnosis of HHT and in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved


Identifying variants within genes known to be associated with HHT and allowing for predictive testing of at-risk family members

Method Name

Custom Sequence Capture and Targeted Next Generation Sequencing followed by qPCR or Polymerase Chain Reaction (PCR) and Supplemental Sanger Sequencing

Reporting Name

Hereditary Hemorrhagic Telan Panel

Specimen Type


Specimen Minimum Volume

Whole blood: 1 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Clinical Information

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular dysplasia characterized by the presence of arteriovenous malformations (AVM) of the skin, mucosa, and viscera. Small AVM, or telangiectasias, develop predominantly on the face, oral cavity, and hands, and spontaneous, recurrent epistaxis (nose bleeding) is a common presenting sign.


Symptomatic telangiectasias occur in the gastrointestinal tract of about 30% of HHT patients. Additional serious complications associated with HHT include transient ischemic attacks, embolic stroke, heart failure, cerebral abscess, massive hemoptysis, massive hemothorax, seizure, and cerebral hemorrhage. These complications are a result of larger AVM, which are most commonly pulmonary, hepatic, or cerebral in origin, and occur in approximately 30%, 40%, and 10% of individuals with HHT, respectively.


HHT is inherited in an autosomal dominant manner and occurs with wide ethnic and geographic distribution. The overall incidence of HHT in North America is estimated to be between 1 in 5,000 and 1 in 10,000. Penetrance seems to be age related, with increased manifestations occurring over one's lifetime. For example, approximately 50% of diagnosed individuals report having nosebleeds by age 10 years, increasing to 80% to 90% by age 21 years, and as many as 90% to 95% of affected individuals eventually developing recurrent epistaxis.


HHT is phenotypically heterogeneous both between families and amongst affected members of the same family. Furthermore, complications associated with HHT have variable ranges of age of onset. Thus, HHT can be diagnostically challenging. Genetic testing allows for the confirmation of a suspected genetic disease. Confirmation of a diagnosis allows for proper treatment and management of the disease, preconception or prenatal counseling, and family counseling. In addition, it has been estimated that genetic screening of suspected HHT individuals and their families is more economically effective than conventional clinical screening.


Two genes are most commonly associated with HHT: the endoglin gene (ENG), and the activin A receptor, type II-like 1 gene (ACVRL1 or ALK1). ENG and ACVRL1 encode membrane glycoproteins involved in transforming growth factor-beta signaling related to vascular integrity. Variants in ENG are associated with HHT type 1 (HHT1), which has been reported to have a higher incidence of pulmonary AVM, whereas ACVRL1 variants occur in HHT type 2 (HHT2), which has been reported to have a higher incidence of hepatic AVM.


The majority of variants in ENG and ACVRL1 are missense, nonsense, splice site, or small intragenic deletions and insertions. Approximately 10% of ENG and ACVRL1 variants are large genomic deletions and duplications (also known as dosage alterations). Approximately 60% to 80% of patients with HHT will have a variant detected in ENG or ACVRL1.


Pathogenic variants in the SMAD4 gene are the third most common identifiable cause of HHT, accounting for approximately 10% of HHT patients who test negative for ENG and ACVRL1, and approximately 1% to 2% of total HHT cases. Pathogenic SMAD4 variants cause autosomal dominant juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JPHT), which includes features of juvenile polyposis syndrome (JPS) and HHT. JPS is characterized by hamartomatous polyps of the gastrointestinal tract and increased risk of gastrointestinal cancer. SMAD4 variants have also been detected in families presenting with JPS or HHT only.


Pathogenic variants in the GDF2 gene (also known as BMP9) are a rare cause of HHT. In a study of 191 individuals with clinically suspected HHT and no variants in ENG, ACVRL1, or SMAD4, 3 unrelated individuals were found to carry a rare missense variant in GDF2. 


Pathogenic variants in the RASA1 gene cause capillary malformation-arteriovenous malformation syndrome (CMAVM). CMAVM is characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations mostly localized to the face and limbs. Patients may also have arteriovenous malformations (AVM) and arteriovenous fistulas (AVF). In some cases, pathogenic RASA1 variants may be found in individuals clinically suspected to have HHT. Individuals with a pathogenic RASA1 variant may have a clinical diagnosis of Parkes Weber syndrome (PWS), with multiple micro-AVF associated with a cutaneous capillary stain and excessive soft tissue and skeletal growth of an affected limb.


Table1.  Genes included in the HHT Gene Panel

Gene Symbol (alias)






Activin A receptor like type 1



Telangiectasia, hereditary hemorrhagic, type 2





Telangiectasia, hereditary hemorrhagic, type 1


Growth differentiation factor 2



Telangiectasia, hereditary hemorrhagic, type 5


RAS p21 protein activator 1



Capillary malformation-arteriovenous malformation, Parkes Weber syndrome


SMAD family member 4



Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Myhre syndrome

AD: autosomal dominant

AR: autosomal recessive

Reference Values

An interpretive report will be provided.


Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Clinical Reference

1. McDonald J, Pyeritz RE: Hereditary Hemorrhagic Telangiectasia. In GeneReviews. Edited by Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. Accessed 2/16/18. Available at

2. Larsen Haidle J, Howe JR: Juvenile Polyposis Syndrome. In GeneReviews. Edited by Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. Accessed 2/16/18. Available at

3. Bayrak-Toydemir P, Stevenson D: RASA1-Related Disorders. In GeneReviews. Edited by Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. Accessed 2/16/18. Available from:

4. Cohen JH, Faughnan ME, Letarte M, et al: Cost comparison of genetic and clinical screening in families with hereditary hemorrhagic telangiectasia. Am J Med Genet A 2005 Aug 30;137(2):153-160

5. Sabba C, Pasculli G, Lenato GM, at al: Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007 Jun;5(6):1149-1157 

6. Abdalla SA, Letarte M: Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006 Feb;43(2):97-110

7. Guttmacher AE, Marchuk DA, White RI Jr: Hereditary hemorrhagic telangiectasia. N Engl J Med 1995 Oct 5;333(14):918-924

8. Bayrak-Toydemir P, Mao R, Lewin S, et al: Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med 2004;6:175-191

Day(s) and Time(s) Performed

Wednesday; Varies

Analytic Time

2 weeks

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information


81406 x 2

LOINC Code Information

Test ID Test Order Name Order LOINC Value
HHTGP Hereditary Hemorrhagic Telan Panel 35474-6


Result ID Test Result Name Result LOINC Value
601723 Gene(s) Evaluated 36908-2
601724 Result Summary 50397-9
601725 Result Details 82939-0
601726 Interpretation 69047-9
601727 Additional Information 48767-8
601728 Method 49549-9
601729 Disclaimer 62364-5
601730 Reviewed By 18771-6
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