Test Catalog

Test Name

Test ID: HHTGP    
Hereditary Hemorrhagic Telangiectasia Gene Panel

Useful For Suggests clinical disorders or settings where the test may be helpful

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

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing as well as supplemental Sanger sequencing to evaluate the genes listed on this panel.

 

Additionally, NGS is used to test for the presence of large deletions and duplications in a subset of genes.

 

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

-KVAR1 / Known Variant Analysis-1 Variant

-KVAR2 / Known Variant Analysis-2 Variants

-KVAR3 / Known Variant Analysis-3+ Variants.

Contact Mayo Medical Laboratories to confirm the appropriate test code for targeted testing if testing for a gene not included on this panel.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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)

Protein

OMIM

Inheritance

Phenotype/Disorder

ACVRL1

Activin A receptor like type 1

601284

AD

Telangiectasia, hereditary hemorrhagic, type 2

ENG

Endoglin

131195

AD

Telangiectasia, hereditary hemorrhagic, type 1

GDF2

Growth differentiation factor 2

605120

AD

Telangiectasia, hereditary hemorrhagic, type 5

RASA1

RAS p21 protein activator 1

139150

AD

Capillary malformation-arteriovenous malformation, Parkes Weber syndrome

SMAD4

SMAD family member 4

600993

AD

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Myhre syndrome

AD: autosomal dominant

AR: autosomal recessive

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have involvement of 1 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 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. 

Clinical Reference Recommendations for in-depth reading of a clinical nature

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 www.ncbi.nlm.nih.gov/books/NBK1351/

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 www.ncbi.nlm.nih.gov/books/NBK1469/

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: 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

Special Instructions Library of PDFs including pertinent information and forms related to the test