Test Id : HHTGP

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Mutation, Targeted Testing, Varies.

Specimen preferred to arrive within 96 hours of collection.

1. Hereditary Hemorrhagic Telangiectasia (HHT) Gene Testing Patient Information (T650) is strongly recommended, but not required, to be filled out and sent with the specimen. This information aids in providing a more thorough interpretation of test results. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Include physician name and phone number with specimen.

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

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. Do not aliquot.

Specimen Stability Information: Ambient (Preferred) 4 days/Refrigerated 14 days

Specimen Type: Extracted 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

• Informed Consent for Genetic Testing
• Hereditary Hemorrhagic Telangiectasia (HHT) Gene Testing Patient Information
• Informed Consent for Genetic Testing (Spanish)

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. Hereditary Hemorrhagic Telangiectasia (HHT) Gene Testing Patient Information (T650) is recommended. See Special Instructions.

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

1 mL

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

This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate for variants in the ACVRL1, ENG, GDF2, RASA1, and SMAD4 genes.

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

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 5000 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.

Genes included in this panel

AD: autosomal dominant

AR: autosomal recessive

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.(1) 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 Correlations:

Some individuals who have involvement of one or more of the genes on the panel may have a variation that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of hereditary hemorrhagic telangiectasia (HHT) or a related disorder.

Test results should be interpreted in context of clinical findings, family history, and other laboratory data.

Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

If testing was performed because of a family history of HHT or a related disorder, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual would allow for more informative testing of at-risk individuals.

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. Additionally, rare alterations (ie, polymorphisms) may be present that could lead to false-negative or false-positive results.

If the patient has had an allogeneic blood or marrow transplant or a recent (ie, less than 6 weeks from time of sample collection) heterologous blood transfusion, these results may be inaccurate due to the presence of donor DNA.

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of this patient's results. 

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

2. McDonald J, Pyeritz RE: Hereditary hemorrhagic telangiectasia. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews [Internet]. University of Washington, Seattle; 2000. Updated February 2, 2017. Accessed February 16, 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1351/

3. Larsen Haidle J, Howe JR: Juvenile polyposis syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews [Internet]. University of Washington, Seattle; 2003. Updated March 9, 2017 Accessed February 16, 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1469/

4. Bayrak-Toydemir P, Stevenson D: Capillary Malformation-arteriovenous Malformation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews [Internet]. University of Washington, Seattle; 2011. Updated September 12, 2019. Accessed September 13, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK52764/

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

• Informed Consent for Genetic Testing
• Hereditary Hemorrhagic Telangiectasia (HHT) Gene Testing Patient Information
• Informed Consent for Genetic Testing (Spanish)

Next-generation sequencing (NGS) is performed using an Illumina instrument with paired-end reads. The DNA is prepared for NGS using a custom Agilent SureSelect Target Enrichment System. Data is analyzed with a bioinformatics software pipeline for sequence variants and the presence of large intragenic deletions and duplications. Supplemental Sanger sequencing or quantitative polymerase chain reaction (qPCR) may be performed occasionally in regions where NGS is insufficient for data capture or not specific enough to correctly identify a variant. Sanger sequencing or qPCR may also be used for confirmatory testing.(Unpublished Mayo method)

Genes analyzed: ACVRL1, ENG, GDF2, RASA1, and SMAD4.

Monday

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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 US Food and Drug Administration.

81479

81406 x 2

Sample Reports

Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports

International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports