Genetic Testing for HHT

What is a genetic test?

Genetic testing is a type of laboratory test used to diagnose inherited diseases like HHT. DNA (genetic material carried in cells) is extracted from a small sample of blood or saliva and analyzed to identify a change (mutation) in one of the HHT genes. Once genetic testing has established the gene mutation which causes HHT within a particular family, this information can be used to help diagnose other members of the family.

Cure HHT strongly encourages individuals and families to arrange genetic testing through a health care provider who understands all of the complexities and limitations of genetic testing for HHT.  In most cases this means having an appointment with a medical geneticist or genetic counselor.

Important Note: Genetic testing technologies have advanced over time, and will continue to improve in the future. People from HHT families in which a mutation has not been identified, or was considered to be of uncertain significance, should periodically check back with the testing laboratory or a genetics professional to find out if additional analysis would be useful.

HHT-associated genes

  • 80% of people who meet the clinical diagnostic criteria for HHT are found to have a mutation in either the ENG (HHT type 1) or ACVRL1 (HHT type 2) gene
  • 3-5% of clinically diagnosed individuals test positive for a mutation in the SMAD4 gene, which causes a combined syndrome of HHT and Juvenile Polyposis
  • About 10-15% of patients will not have a mutation detected in a known HHT gene, and in these cases a diagnosis is made based on clinical evaluation alone*
  • Although a handful of people in the world with HHT have been reported to have a mutation in the BMP9/GDF2 gene, it is so rare (<<1%) that it is not typically a part of routine genetic testing for HHT.

*Because 15% of people diagnosed with HHT do not have a mutation in one of the identified HHT genes, a negative genetic diagnosis does not necessarily mean that a person does not have HHT. There are likely other genes that cause the symptoms of HHT that have not yet been identified.

Why get a genetic test?

  1. If you have been clinically diagnosed with possible HHT according to the Curacao diagnostic criteria, genetic testing may be done to establish or confirm a diagnosis.
  2. If you have been clinically diagnosed with definite HHT, genetic testing may be done to identify the affected gene in order to accurately test other family members.
  3. If you have a direct relative who has been genetically diagnosed, genetic testing would be done to test for the presence or absence of the mutation that was identified in your family member. The presence of the family HHT-causing mutation would prove HHT, while its absence would rule it out.

Unless HHT is ruled out by genetic testing, all children of a parent with HHT should be screened for brain and lung AVMs. For young children, these procedures require sedatives, or general anesthesia, but they are critical to establishing proper diagnosis and care. If an HHT mutation has already been identified in a family, genetic testing of at-risk family members for the known mutation will identify which family members have HHT and therefore need to be screened for internal AVMs.

Possible results of a genetic test for HHT

If you are the first member of your family to be genetically tested to identify the gene mutation that causes HHT in your family, there are three possible results:

  1. Positive for a “pathogenic” (HHT- causing) mutation; the laboratory found a mutation (change in DNA) in one of the HHT-associated genes, and the mutation is thought to cause HHT. This means that you have been genetically diagnosed with HHT and your DNA results can be used to help identify other affected family members.
  2. Negative. In most scenarios, this means a person does not have HHT. In 10-15% of cases, a negative result indicates that a person has HHT, but the affected gene is still unknown.
  3. Variant of Uncertain Significance. This means a genetic variant is detected in one of the HHT genes, but it is not possible to confirm that it is the cause of HHT.

If you are being genetically tested for the specific HHT-causing mutation that was identified in a family member, there are two possible results:

  • Positive. This result means that the family HHT gene mutation is present, and that you have HHT.
  • Negative. This result means that the family HHT gene mutation is not present, and that you did not inherit HHT.