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. 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. 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. Each of these two genes is responsible for approximately 30-40% of HHT cases. Full gene sequence analyses with gross deletion/duplication testing of both genes detects mutations in 80-85% of patients. The SMAD4 gene, which can be tested separately or as a reflex test, accounts for 2-3% of cases HHT and adds juvenile polyposis to the phenotype in most cases.

The Ambry Test: HHT AMPLIFIED™ is concurrent sequence analyses of the ENG and ACVRL1 genes with reflex to gross deletion/duplication analyses of both genes if no mutation is found by sequence analysis. Turn-around-time is 14-28 days. If sequencing detects a known disease-causing mutation, the result is informative and deletion/duplication testing is cancelled. The turn-around-time is reduced to 14-21 days and a price discount is applied.

The Ambry Test: SMAD4-Related HHT begins with sequence analysis of exons 8-11, the exons in which HHT-related mutations have been reported to date. If negative, testing continues automatically with sequencing of the remaining exons. This test is appropriate for suspected HHT patients who have tested negative for mutations in ENG and ACVRL1.

Sequence analysis of ENG or ACVRL1 individually, familial mutation testing, and analysis for deletions or duplications of the ENG and ACVRL1 genes (both genes analyzed together) are all available by request.

The following CPT Codes for the Ambry Test reflects Ambry Genetics’ interpretation of CPT coding requirements based on AMA guidelines:

Ambry Test: HHT AMPLIFIED
83891, 83894, 83898, 83900, 83901, 83904, 83909, 83912

Ambry Test: SMAD4-Related HHT
83891, 83894, 83898, 83904, 83909, 83912

CPT codes are provided only as a guide to assist you in billing. CPT coding is the sole responsibility of the billing party.

Disclaimer for ENG and ACVRL1:

This test was developed and its performance characteristics were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform non-waived testing. The Ambry Test: HHT AMPLIFIED analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions, small indels and gross deletions and insertions. It is not intended to analyze the following types of mutations: gross rearrangements, deep intronic variations, and other unknown abnormalities. The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. The Ambry Test: HHT AMPLIFIED is designed and validated to be capable of detecting about 99% of described mutations in ENG and ACVRL1 (considering less than 1% to be the other types of mutations). These detectable mutations account for 80-85% of cases of HHT. HHT is a complex clinical disorder, which in most cases is due to alterations in ENG or ACVRL1 genes generally detected by the Ambry Test: HHT AMPLIFIED except as noted above. Mutations in other genes such as SMAD4 or the regions not tested by the Ambry Test: HHT AMPLIFIED can also give rise to clinical conditions similar or identical to HHT. Although molecular tests are highly accurate, rare diagnostic errors may occur. Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, clerical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature.

Disclaimer for SMAD4:

This test was developed and its performance characteristics were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing. The Ambry Test: SMAD4 analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions, and small indels. It is not intended to analyze the following types of mutations: gross deletions and insertions, gross rearrangements, deep intronic variations, and other unknown abnormalities. The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. The Ambry Test: SMAD4 is designed and validated to be capable of detecting about 94% of described mutations in SMAD4 (considering less than 6% to be the other types of mutations). These detectable mutations account for approximately 22% of JPS cases and 2-3% of HHT. JPS and HHT are complex clinical disorders, which in some cases are due to alterations in SMAD4 gene generally detected by the Ambry Test: SMAD4 except as noted above. Mutations in other genes or the regions not tested by the Ambry Test: SMAD4 can also give rise to clinical conditions similar to JPS or HHT. Although molecular tests are highly accurate, rare diagnostic errors may occur. Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, clerical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature.