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HelpTest ID: HHTGG Hereditary Hemorrhagic Telangiectasia and Vascular Malformations Gene Panel, Varies
Ordering Guidance
Customization of this panel and single gene analysis for any gene present on this panel are available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.
Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.
Shipping Instructions
Necessary Information
Prior Authorization is available, but not required, for this test. If proceeding with the prior authorization process, submit the required form with the specimen.
Specimen Required
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For information about testing patients who have received a bone marrow transplant, call 800-533-1710.
Specimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Green top (Sodium heparin)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.
Specimen Type: Saliva
Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.
Supplies: Saliva Collection Kit (T786)
Specimen Volume: 1 Swab
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient (preferred) 30 days/Refrigerated 30 days
Additional information: Saliva specimens are acceptable but not recommended. Due to lower quantity/quality of DNA yielded from saliva, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.
Specimen Type: Cultured fibroblasts
Source: Skin
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and/or extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Tissue biopsy
Supplies: Hank's Solution (T132)
Container/Tube: Sterile container with sterile Hank's balanced salt solution, Ringer's solution, or normal saline
Specimen Volume: 0.5 to 3 cm(3) or larger
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Blood spot
Supplies: Card-Blood Spot Collection (Filter Paper) (T493)
Container/Tube:
Preferred: Collection card (Whatman Protein Saver 903 Paper)
Acceptable: PerkinElmer 226 filter paper or blood spot collection card
Specimen Volume: 2 to 5 Blood spots
Collection Instructions:
1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect Dried Blood Spot Samples.
2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.
3. Do not expose specimen to heat or direct sunlight.
4. Do not stack wet specimens.
5. Keep specimen dry.
Specimen Stability Information: Ambient (preferred)/Refrigerated
Additional Information:
1. Blood spot specimens are acceptable but not recommended. Multiple extractions will be required to obtain sufficient yield for supplemental analysis, and there is significant risk for test failure due to insufficient DNA.
2. Due to lower concentration of DNA yielded from blood spot, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.
3. For collection instructions, see Blood Spot Collection Instructions
4. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)
5. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)
Specimen Type: Extracted DNA
Container/Tube:
Preferred: Screw Cap Micro Tube, 2mL with skirted conical base
Acceptable: Matrix tube, 1mL
Collection Instructions:
1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated
Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.
Forms
1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file.
The following documents are available:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
2. Hereditary Hemorrhagic Telangiectasia and Vascular Malformations Gene Panel Patient Information
4. If not ordering electronically, complete, print, and send a Cardiovascular Test Request Form (T724) with the specimen.
Useful For
Providing a genetic evaluation for patients with a personal or family history suggestive of hereditary hemorrhagic telangiectasia (HHT), cerebral cavernous malformation (CCM), capillary malformation-arteriovenous malformation syndrome (CV-AVM), or other hereditary vascular malformation syndromes of germline origin
Establishing a diagnosis of HHT, CCM, CM-AVM, or other hereditary vascular malformation syndromes of germline origin
Genetics Test Information
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 12 genes associated with hereditary hemorrhagic telangiectasia (HHT), cerebral cavernous malformation (CCM), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and other hereditary vascular malformation syndromes of germline origin: ACVRL1, BMPR2, CCM2, ENG, EPHB4, GDF2, GLMN, KRIT1, PDCD10, RASA1, SMAD4, and TEK. See Targeted Genes and Methodology Details for Hereditary Hemorrhagic Telangiectasia and Vascular Malformations Gene Panel and Method Description for additional details.
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for HHT, CCM, CM-AVM, and other hereditary vascular malformation syndromes of germline origin.
Method Name
Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing
Reporting Name
HHT and Vascular Gene PanelSpecimen Type
VariesSpecimen Minimum Volume
See Specimen Required
Specimen Stability Information
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Clinical Information
Hereditary vascular malformation syndromes include a group of genetic conditions characterized by abnormal blood vessel development. These syndromes can be of germline or somatic origin. This gene panel is restricted to analysis of genes associated with vascular malformation syndromes of germline origin.
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.(1) HHT has an estimated prevalence of 1:5000 and is primarily caused by heterozygous, disease-causing variants in the ACVRL1 and ENG genes. Rarely, HHT can be caused by disease-causing variants in the GDF2 gene (also known as BMP9). Additionally, SMAD4 disease-causing variants cause autosomal dominant juvenile polyposis/HHT syndrome, which includes features of juvenile polyposis syndrome and HHT.(2) An overlapping pulmonary arterial hypertension and HHT phenotype have also been reported in association with the BMPR2 gene.(3,4)
Familial cerebral cavernous malformation (CCM) is an autosomal dominant condition characterized by structurally abnormal capillaries in the central nervous system leading to an increased risk of cerebral hemorrhage.(5) The estimated prevalence of familial CCM ranges from 1:3300 to 1:10,000,(5) and the condition displays age-related penetrance with up to 50% of individuals remaining symptom free throughout their life.(5,6) Disease-causing variants in three genes have been associated with familial CCM: KRIT1, CCM2, and PDCD10.
Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant condition primarily characterized by capillary malformations localized to the dermis of the face and limbs, AVM or arteriovenous fistulas of the skin, muscle, bone, spine, and brain, and Parkes Weber syndrome.(6) The prevalence of CM-AVM has been estimated in Northern European cohorts at approximately 1:100,000, with penetrance estimated at 90% to 99%.(6) Approximately 60% of cases of CM-AVM can be attributed to disease-causing variants in the EPHB4 and RASA1 genes. The genetic etiology remains unknown in approximately 40% of cases.(6)
Hereditary glomuvenous malformation is a rare autosomal dominant condition characterized by multiple venous malformations within the glomerulus of the kidney. The condition is associated with germline disease-causing variants in the GLMN gene. However, it is thought that a second, somatic (acquired) variant on the second allele, or acquired uniparental disomy, is required for the development of venous malformations.(7,8)
Multiple cutaneous and mucosal venous malformations (also known as cutaneomucosal venous malformation: VMCM) is an autosomal dominant condition characterized by small multifocal cutaneous and mucosal vascular malformations that typically present at birth.(9) These lesions are usually asymptomatic but may become painful if they are large enough to impact the underlying muscle tissue. The prevalence of this condition is unknown but thought to be rare. VMCM is associated with disease-causing variants in the TEK gene, and penetrance is estimated at 90% in individuals with a known genetic etiology.(9)
Reference Values
An interpretive report will be provided.
Interpretation
All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(10) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Clinical Reference
1. Faughnan ME, Mager JJ, Hetts SW, et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2020;173(12):989-1001. doi:10.7326/M20-1443
2. McDonald J, Stevenson DA. Hereditary hemorrhagic telangiectasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds: GeneReviews [Internet]. University of Washington, Seattle; 2000. Updated November 24, 2021. Accessed December 5, 2024. Available at www.ncbi.nlm.nih.gov/books/NBK1351/
3. Rigelsky CM, Jennings C, Lehtonen R, Minai OA, Eng C, Aldred MA. BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia. Am J Med Genet A. 2008;146A(19):2551-2556. doi:10.1002/ajmg.a.32468
4. Ye F, Jiang W, Lin W, et al. A novel BMPR2 mutation in a patient with heritable pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia: A case report. Medicine (Baltimore). 2020;99(31):e21342. doi:10.1097/MD.0000000000021342
5. Zafar A, Quadri SA, Farooqui M, et al. Familial cerebral cavernous malformations. Stroke. 2019;50(5):1294-1301. doi:10.1161/STROKEAHA.118.022314
6. Bayrak-Toydemir P, Stevenson DA. 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 December 5, 2024. Available at www.ncbi.nlm.nih.gov/books/NBK52764/
7. Brouillard P, Boon LM, Mulliken JB, et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas"). Am J Hum Genet. 2002;70(4):866-874. doi:10.1086/339492
8. Amyere M, Aerts V, Brouillard P, et al. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet. 2013;92(2):188-196. doi:10.1016/j.ajhg.2012.12.017
9. Seront E, Boon LM, Vikkula M. TEK-Related venous malformations. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2008. Updated March 2, 2023. Accessed December 5, 2024. Available at www.ncbi.nlm.nih.gov/books/NBK1967/
10. 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;17(5):405-424. doi:10.1038/gim.2015.30
Day(s) Performed
Varies
Report Available
14 to 21 daysTest Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81406 x3
81479
81479 (if appropriate for government payers)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| HHTGG | HHT and Vascular Gene Panel | 51966-0 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 617296 | Test Description | 62364-5 |
| 617297 | Specimen | 31208-2 |
| 617298 | Source | 31208-2 |
| 617299 | Result Summary | 50397-9 |
| 617300 | Result | 82939-0 |
| 617301 | Interpretation | 69047-9 |
| 617302 | Additional Results | 82939-0 |
| 617303 | Resources | 99622-3 |
| 617304 | Additional Information | 48767-8 |
| 617305 | Method | 85069-3 |
| 617306 | Genes Analyzed | 48018-6 |
| 617307 | Disclaimer | 62364-5 |
| 617308 | Released By | 18771-6 |
Reflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | No | No |
Testing Algorithm
For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
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