Genetic testing is available for families who are affected by HHT. Development of clinical genetic testing for HHT was a long-standing priority of the HHT Foundation and we are grateful for the efforts of the many people who have made this possible.

Testing vs. Screening

Individuals who are known to have HHT need to be screened for internal manifestations of the disease, particularly its lung and brain manifestations. In the past, most members of a family with HHT were encouraged to undergo such screening. There was no way to tell with certainty that someone without visible outward symptoms did not have the disorder. Because sudden and tragic consequences (e.g. stroke, brain hemorrhage, brain abscess) could result if someone with such internal manifestations of HHT was not checked and treated, screening was strongly encouraged for all members of an HHT family.

Now genetic testing is available. This means that those without symptoms, particularly children, can be tested to see if they carry the gene. If they do not, then screening is not necessary. If they do, it certainly will be.

Many families affected by HHT are interested in genetic testing, and are anxious to have the testing done as soon as possible. The information below is meant to answer some of the questions that are asked about genetic testing for HHT. Although genetic testing is usually performed on a blood sample it is not ‘just a simple blood test.’ It actually takes planning and coordination within a family. Our experience is that a family is well served by consulting a genetics clinic in their area, or an HHT Center, for help planning, coordinating and accurately interpreting genetic testing. Very few physicians outside a genetics clinic or HHT center are able to implement and interpret genetic testing for a rare, complex condition such as HHT.

Note: Please click on the link called ‘Understanding the Genetics of HHT’ which provides some background genetic information about HHT. It may be helpful to read this before reading the information below which focuses on the ‘whys and hows’ of clinical genetic testing.

Understanding The Genetics of HHT

What is Genetic Testing for HHT?

Genetic testing for HHT consists of studying the endoglin and ALK-1 genes. It is a specialized type of testing performed in only a few laboratories worldwide. The goal is to find the exact DNA change (mutation) believed to be responsible for HHT in a given family. This process (called sequencing) involves extensive analysis of the genetic code of these two known HHT genes. Once such a mutation has been found in one family member who has a diagnosis of HHT, other family members can be tested to see if they also have this ‘family specific’ HHT mutation. This can allow us to say with a high level of certainty which other family members have inherited HHT. But - there are frequently complexities and uncertainties involved with HHT genetic testing. It often isn’t simply a ‘yes or no’ answer.

Why Is Genetic Testing Useful? If I Already Know That I Have HHT, Why Should I Have Genetic Testing?

If a person already knows that he or she has HHT because of the clinical diagnostic criteria, genetic testing can confirm the diagnosis. (The clinical diagnostic criteria are listed at the end of this section.) Also, knowing which gene is involved can help to predict the likelihood of certain manifestations associated with HHT.

Often the primary reason that genetic testing is useful for someone already diagnosed with HHT is to help other family members in whom the diagnosis of HHT is not certain. Children and young adults with HHT often do not have visible symptoms of HHT yet, but are still at risk for complications from lung AVMs and brain AVMs from the time of birth. Since we recommend specific medical screening tests to detect AVMs as early in life as possible for all individuals with HHT- it is important to know at a young age which family members have actually inherited the HHT gene. In families where an endoglin or ALK-1 gene mutation has already been identified in a family member with HHT, testing other family members for this known mutation will allow the physician to identify which children and other family members really need these medical screening tests to prevent serious complications of HHT such as stroke or brain abscess.

How Is Genetic Testing Done?

Genetic testing is done on a blood sample - shipped to one of the laboratories performing genetic testing for HHT. It is not a type of testing familiar to most primary care doctors and there are only 1 or 2 laboratories per country that perform HHT testing. Results typically take 3-6 weeks and a report is sent to the physician or genetic counselor who arranged for and ordered the testing.

What’s The Best Way To Arrange Genetic Testing For My Family and Myself?

The first person to be tested in a family should always be someone who has a clear and definite clinical diagnosis of HHT. Genetic testing for the first person in a family will involve extensive testing of both the endoglin and ALK-1 genes and will be relatively expensive. But after a mutation is found in one family member, it is easy, and relatively inexpensive, to test other family members to see who else has inherited this same mutation.

Unfortunately, there are HHT families in which the laboratories cannot find the responsible gene mutation in the endoglin or ALK-1 gene. If genetic testing is not able to identify a mutation in a family member who clearly has HHT, it will not be useful to perform genetic testing on other family members.

The HHT Foundation strongly encourages individuals and families to arrange genetic testing through health care providers who understand all of the complexities and limitations of genetic testing for HHT. This can be done by working with one of the HHT Centers or with a genetics clinic in your area. Contact information for HHT Centers can be found at the HHT Foundation website (www.hht.org). If it is too difficult for you to travel to one of the HHT Centers, you can ask your doctor for a referral to a local genetics specialist. Genetics clinics can be found through the website of the National Society of Genetic Counselors (www.nsgc.org).

What Are The Possible Results From Genetic Testing?

The first person tested from a given family will be tested by methods that examine the complete sequence of both the endoglin and ALK-1 genes. There are 3 possible results from this analysis:

1. Positive for a “deleterious” (disease causing) mutation. This result means that the laboratory found a mutation in either endoglin or ALK-1, and that the mutation is one that is known to prevent the endoglin or ALK-1 gene from working properly. This result means that the laboratory has found the cause of HHT in the tested person. Other family members can now be tested to see if they have HHT by having testing to see if they also have this ‘family specific’ mutation.
2. Negative for a significant DNA sequence variation. This result means that the laboratory was not able to find a mutation in the endoglin or ALK-1 gene that could explain the tested person’s HHT. Genetic testing will not be useful for determining which other family members have HHT.
3. Uncertain. The laboratory has found a variation in the DNA sequence of either the endoglin or ALK-1 gene, but cannot be certain whether or not it is the actual cause of the HHT. These kinds of gene variations are found in all genes and they are particularly common in the endoglin and ALK-1 genes. In most cases, this type of ‘uncertain’ result will not be useful for determining which other family members have HHT. Sometimes laboratories are able to do additional testing to try to clarify an ‘uncertain’ result and then are able to reclassify it as ‘positive’.

For additional family members being tested to see if they have inherited a mutation already identified in a family member with HHT, there are 2 possible test results:

1. Positive for the family mutation. This person has inherited the gene mutation known to cause HHT in their family. This person has HHT.
2. Negative for the family mutation. This person has not inherited the gene mutation known to cause HHT in their family and is predicted to be unaffected by HHT and not at risk to pass it to children.

How Could Genetic Testing Fail To Find The Mutation That Causes HHT In Someone Who Clearly Has The Condition?

There are a few possible explanations why this occurs:

1. The person has HHT as a result of a mutation in endoglin or ALK-1 that cannot be detected by current testing techniques.
2. The person has HHT as a result of a mutation in a gene other than endoglin or ALK-1. The endoglin and ALK-1 genes are responsible for most cases of HHT, but there exists solid evidence that there are other rare HHT genes that have not yet been found.
3. The person who was tested does not really have HHT. Some people who have symptoms of HHT may have a different disease. Physicians who are not familiar with HHT may order testing for patients who do not actually have the condition. This is one reason why the HHT Foundation believes it is best if genetic testing is done only after a physician who is experienced with HHT has evaluated someone.

Researchers are working with HHT families in which no mutation has been found using current testing techniques in order to develop additional ways to test the already known HHT genes, as well as to identify additional HHT gene(s).

If A Physician Is Unsure Whether A Patient Has HHT, Can Genetic Testing Help Make a Diagnosis?

This is usually only helpful if a mutation in endoglin or ALK-1 has already been found in a relative who clearly has HHT. As discussed above, there are people with HHT who do not have a detectable mutation in either the endoglin or ALK-1 gene. This means that genetic testing will not determine reliably whether someone has HHT unless the responsible mutation is present and identified in another clearly affected family member. The initial diagnosis of HHT in a family should always rely on a careful and targeted clinical examination, medical history, and a detailed, extended family history taken with specific symptoms of HHT in mind.

CLINCIAL DIAGNOSTIC CRITERIA FOR HHT

The established diagnostic criteria for HHT are:

1. Nosebleeds (epistaxis), which are spontaneous and recurrent may be mild or severe
2. Telangiectases on the skin or mucous membranes (mucocutaneous). Telangiectases are small red spots that blanch under pressure, located at characteristic sites, including the lips, oral cavity, fingers, and nose.
3. Visceral arteriovenous malformations (AVMs), consisting of direct connections between arteries and veins. They may be located in the lungs, brain, liver, spinal cord, or GI tract.
4. A first-degree relative (brother, sister, parent or child) with HHT, based on these diagnostic criteria.

A diagnosis of HHT is considered definite when 3 or more of these features are present, possible or suspected when 2 findings are present, and unlikely with fewer than 2 findings.

There will be cases where a person has some signs of HHT, but their physician is not able to make a definitive diagnosis. In cases like this, a positive test might confirm that someone does have the condition, but a negative test will not rule it out.

What Happens If An HHT Mutation Cannot Be Detected in my Family?

Certain children and others in HHT families without detectable mutations should have medical screening for AVMs because genetic testing cannot be used to tell for sure whether they have HHT.

How Much Will Genetic Testing Cost And Will My Health Insurance Pay For Genetic Testing For HHT?

Testing the first person from a family with the comprehensive analysis of both ALK-1 and endoglin costs well over one thousand dollars. Once a mutation has been identified in a family member with HHT, testing for other family members usually costs a few hundred dollars per person.

Genetic testing is often covered by insurance but it depends on the insurance company and their particular plan. You will have to contact your insurance provider to ask if genetic testing is included in your plan and whether preauthorization is required. HHT centers and genetics clinics may be able to help if pre-authorization is needed because these genetic counselors and physicians have experience with the insurance issues involved in genetic testing.

LABORATORIES OFFERING HHT GENETIC TESTING IN NORTH AMERICA

University of Pennsylvania: Genetic Diagnostic Laboratory
Department of Genetics
415 Curie Blvd.
Philadelphia, PA. 19104-6145
Contact: Barbara Bernhart, Certified Genetic Counselor
http://www.med.upenn.edu/genetics/core-facs/gdl

ARUP Laboratories
500 Chipeta Way
Salt Lake City, UT 84108-1221
Contact: Jamie McDonald, MS, Certified Genetic Counselor
http://www.aruplab.com

HHT Solutions
Toronto Western Hospital
399 Bathurst Street MP 6-210
Toronto, Ontario M5T 2S8
CANADA
Contact: Jeanne McKay
Email: jmckay@uhnres.utoronto.ca
http://www.hhtsolutions.org
Hospital for Sick Children
Molecular Genetics Laboratory
Department of Peadiatric
555 University Avenue
Ste. EW6-520
Toronto, Ontario M5G 1X89
CANADA
http://www.sickkids.ca/molecular

My Family Health Portrait

The Surgeon General launched a national initiative to encourage all American families to learn more about their family health histories. Knowing your family’s medical history can save your life.

The Surgeon General has created a new computerized tool to help make it fun and easy to create a sophisticated portrait of your family’s health. This tool is called ‘My Family Health Portrait,’ and can be downloaded for free and installed on your own computer.

This tool will help you organize your family tree and help you identify your health disorders that may have moved from one generation of your family to the next. The finished product will print out a graphical representation of your family’s generations-especially important for HHT families. To create a Family Health Portrait online go to: www.hhs.gov/familyhistory/