HHT AMPLIFIED™ & SMAD4-Related HHT
Hereditary Hemorrhagic Telangiectasia (HHT or Osler-Weber-Rendu disease) is an autosomal dominant disorder of blood vessel formation.
PrintHereditary Hemorrhagic Telangiectasia (HHT or Osler-Weber-Rendu disease) is an autosomal dominant disorder of blood vessel formation.
Mutations in ENG cause HHT Type 1, which has a high prevalence of pulmonary arteriovenous malformations (AVMs). Mutations in ACVRL1 cause HHT Type 2, which causes fewer pulmonary and cerebral AVMs than Type 1 but more hepatic AVMs. Each of these two genes is responsible for approximately 30-40% of Hereditary Hemorrhagic Telangiectasia cases. Full Gene Sequence Analysis with gross Deletion/Duplication Analysis of both genes detects mutations in 80-85% of patients. The SMAD4 gene accounts for 2-3% of cases of HHT and adds juvenile polyposis to the phenotype in most cases.
The HHT AMPLIFIED™ test includes concurrent sequence analysis of the ENG and ACVRL1 genes with reflex testing to gross Deletion/Duplication Analysis of both genes if no mutation is found by Gene Sequence Analysis. SMAD4 sequence analysis can be ordered separately or in any combination with ENG and ACVRL1 as indicated. It begins with analysis of exons 8-11 of SMAD4, in which most HHT-related mutations in SMAD4 occur, and if no mutation is detected, the remaining exons are sequenced.
Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu disease) is an autosomal dominant disorder of blood vessel formation affecting 1/8000-1/10,000 people.1,2 Abnormal direct connections of arteries and veins in larger vessels manifest as arteriovenous malformations (AVMs) most often in the lungs, liver, and brain. Smaller vessel abnormalities result in telangiectases, especially on the face, hands, and mucous membranes. The most common and often first symptom is recurrent epistaxis (nosebleeds) beginning in early adolescence. Gastrointestinal bleeding due to intestinal telangiectases is common in patients over 40 and like epistaxis, it can become a significant medical concern. The age of onset and severity of symptoms vary widely. HHT is treated symptomatically and managed through surveillance for AVMs and preventive care.
Genes associated with HHT function in TGF-beta signaling. Mutations in the endoglin gene (ENG) cause HHT type 1, which has a high prevalence of pulmonary AVMs.1 Mutations in the activin receptor-like kinase 1 gene (ACVRL1 or ALK1) cause HHT type 2, which causes fewer pulmonary and cerebral AVMs than type 1 but more hepatic AVMs.1 Each of these two genes is responsible for approximately 30-40% of HHT cases.1,3 Full gene sequence analyses with gross deletion/duplication testing of both genes detects mutations in 80-85% of patients.1,4,5,6 The SMAD4 gene accounts for 2-3% of cases of HHT and adds juvenile polyposis to the phenotype in most cases.7,8
Genetic testing enables:
- confirmation of diagnosis of HHT in symptomatic individuals
- determination of disease status in at-risk family members
- early detection of AVMs
- opportunity for management to prevent or minimize complications of HHT
The Ambry Test: HHT AMPLIFIED includes concurrent sequence analyses of the ENG and ACVRL1 genes with reflex testing to gross deletion/duplication analyses of both genes if no mutation is found by sequence analysis. PCR- based double-stranded automated sequencing is performed in the sense and antisense directions for exons 1-14 (15 exons total) of ENG and exons 2-10 of ACVRL1, plus at least 20 bases into the 5’ and 3’ ends of all the introns. If no mutation is detected, analysis of both genes for gross deletions/duplications of any exon is performed by MLPA®.
The Ambry Test: SMAD4-Related HHT begins with double-stranded automated sequencing in the sense and antisense directions of exons 8-11 of SMAD4 plus at least 20 bases into the 5’ and 3’ ends of the corresponding introns. Exons 8-11 are the exons in which HHT-related mutations have been reported to date. If no mutation is detected, testing continues automatically with sequencing of the remaining exons 1-7 plus at least 20 bases into the 5’ and 3’ ends of the corresponding introns.
Sequence analysis of ENG or ACVRL1 individually is available, as is analysis just for deletions or duplications (both genes are analyzed together). SMAD4 testing can be ordered separately or in any combination with ENG and ACVRL1 as indicated. Specific mutation analysis of any of the three genes for individual mutations known to be in the family is available.
As stated before, HHT AMPLIFIED (full gene sequence analyses with gross deletion/duplication testing of ENG and ACVRL1) detects mutations in 80-85% of patients.1,4,5,6 SMAD4 detectable mutations are found in 2-3% of cases of HHT and up to 10% of those patients that have tested negative for mutations in the other two genes.7
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into OrageneTM DNA Self Collection container. Store and ship at room temperature.
DNA: Send 20 μg in TE at 50-100 ng/μl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case
| Test Code | Technique | CPT Codes |
|---|---|---|
| 1680 | HHT ACVRL1, ENG Gene Sequence Analysis and Deletion / Duplication | 83891x1, 83894x25, 83898x24, 83904x29, 83900x1, 83901x27, 83909x29, 83912x32 |
| 1681 | HHT Deletion / Duplication (ACVRL1, ENG) | 83891x1, 83894x1, 83900x1, 83901x27, 83909x1, 83912x1 |
| 1683 | HHT Gene Sequence Analysis (ACVRL1, ENG) | 83891x1, 83894x25, 83898x24, 83904x29, 83909x29, 83912x2 |
| 1684 | SMAD4 Gene Sequence Analysis | 83891x1, 83894x11, 83898x10, 83904x15, 83909x15, 83912x1 |
| 1686 | HHT SMAD4 Exons 8-11 Sequence | 83891x1, 83894x5, 83898x4, 83904x8, 83909x8, 83912x1 |
| 1689 | ENG Gene Sequence Analysis | 83891x1, 83894x16, 83898x15, 83904x20, 83909x20, 83912x1 |
| 1690 | ACVRL1 Gene Sequence Analysis | 83891x1, 83894x10, 83898x9, 83904x18, 83909x18, 83912x1 |
| 8660 | HHT Sequence Reflex Option (ACVRL1, ENG, Deletion / Duplication, SMAD4) | 83891x1, 83894x35, 83898x34, 83904x42, 83900x1, 83901x27, 83909x42, 83912x4 |
| 8662 | HHT Sequence Concurrent (ACVRL1, ENG, Deletion / Duplication, SMAD4) | 83891x1, 83894x35, 83898x34, 83904x42, 83900x1, 83901x27, 83909x42, 83912x4 |
| Call 1 | HHT Single Gene Deletion / Duplication Analysis | 83891x1, 83894x1, 83900x1, 83901x13, 83909x1, 83912x1 |
| Technique | Days |
|---|---|
| HHT ACVRL1, ENG Gene Sequence Analysis and Deletion / Duplication | 10-21 |
| HHT Deletion / Duplication (ACVRL1, ENG) | 7-14 |
| HHT Gene Sequence Analysis (ACVRL1, ENG) | 10-21 |
| SMAD4 Gene Sequence Analysis | 10-21 |
| ENG Gene Sequence Analysis | 10-21 |
| ACVRL1 Gene Sequence Analysis | 10-21 |
| HHT Sequence Reflex Option (ACVRL1, ENG, Deletion / Duplication, SMAD4) | 14-42 |
| HHT Sequence Concurrent (ACVRL1, ENG, Deletion / Duplication, SMAD4) | 14-28 |
| HHT Single Gene Deletion / Duplication Analysis | 7-14 |
1 Prigoda NL et al. J Med Genet. 2006;43:722-728.
2 Marchuk DA et al. Am J Hum Genet. 1996;59:95-102.
3 Bayrak-Toydemir P et al. Genet Med. 2004;6:175-191.
4 Lesca G et al. Genet Med. 2006;27:598.
5 Schulte C et al. Human Mutat. 2005;25:595.
6 Cymerman U et al. Human Mutat. 2003;21:482-492.
7 Gallione CJ et al. J Med Genet. 2006;43:793-797.
8 Gallione CF et al. Lancet. 2004;363:852-859.