Q&A About DNA Testing

I was asked to organize my talk around the questions that are frequently asked of the people who staff the VHLFA hotline number. I would like to thank the 800 hotline volunteers for compiling this list of questions. Altheada Johnson, Eva Logan, Peggy M., Barbara Redding.

First I would like to do a quick review of some genetic concepts. We all have 46 chromosomes in every cell, and these contain all our genes. These are all in pairs, one chromosome in each pair comes from our mother, and the other from our father. And we each are estimated to have somewhere in the ballpark of 50,000 to 80,000 genes in total, so each chromosome has hundreds or even thousands of genes on its length, like beads on a string, lined up along the chromosome, next to one another. The function of genes is typically to produce a protein, or a protein sub-unit, that has some important cell function in the cell, that will affect its growth or activity in one way or another.

Sometimes when I’m talking with people there is some confusion. It sounds like we are discussing whether you have a gene or not. But in reality we all have two copies of the VHL gene. The question is whether you have a mutation in one copy of the gene or not – any change in the gene sequence that alters the information that the gene provides for production of the normal protein product. Some mutations in genes are "silent," meaning they don’t seem to have any harmful effect on the function of the protein product and therefore don’t have any impact on cell function and health. There are others that we think of as deleterious, having a harmful effect, and believed to be associated with disease. There are others still that we think of as leading to normal human variation — differences in eye color, hair color and so on, that make us a little bit different from each other. In fact, it is estimated that each of us has at least 10-15 harmful alterations in a variety of different genes, but most of us don’t know what those genes are or what possible harmful effect those genes might have on us.

VHL is an autosomal dominant condition. That means that only one copy of the gene pair has the alteration in it. Each person has one copy from Mom and one copy from Dad. Similarly when we have children we pass only one copy in each of our gene pairs to a child. If a person has only one altered gene — one healthy copy and one altered copy — one of those two copies is passed to each child. That’s the fifty-fifty chance of passing VHL to a child. It won’t skip a generation, and suddenly appear in a grandchild. It’s either there or it’s not. It may appear to skip a generation — we may not have seen the effects for some reason — but it’s there. Because VHL is on chromosome 3, which is not one of the sex chromosomes, it can be passed equally to male and female children.

VHL is in the category of tumor-suppressor genes that control the growth of specific kinds of cells. There is an increased chance of tumors when both copies of the VHL gene are inactivated or have mutations in a cell. People with VHL have inherited one altered copy of the VHL gene, and then at random, for reasons that we don’t yet understand, in various tissue types the second copy of the gene may become inactivated and a tumor will appear.

Another example is to think of this as brakes on a car. Most cars have two sets of brakes: front brakes and back brakes. If a person has inherited a mutation in a tumor-suppressor gene, one of those sets of brakes doesn’t work. The second set does work, so the car can still stop. It’s only when the second set of brakes is knocked out that the car can’t stop.

Because a person with VHL is born with an alteration in every cell, we can see tumors in various tissues. But again we don’t understand yet what these other causes are that explain why tumors occur in one tissue rather than another, or at one stage of life rather than another.

Myths

Someone who has two unaffected children might be led to believe that they no longer have to worry about VHL. "It hasn’t happened twice, so it’s not going to happen again." Not true. It’s 50/50 every time, with each pregnancy. Just as in coin-flipping you can get two heads in a row, but it doesn’t mean you won’t get tails on the next flip.

Some people may believe that VHL only occurs in one gender, based on their own family experience. But this is a random occurrence. VHL occurs equally in males and females.

Some people believe that VHL only happens at later stages of life. Not true. Children can have issues from very young ages.

Conversely, if someone has reached a certain age, and haven’t had symptoms, then they sometimes believe they must be in the clear. Not necessarily so. There are people who have been diagnosed for the first time in their 70’s or 80’s.

Some families believe that they will have only one of the VHL issues, but they may not have seen it yet in their relatives, but we don’t yet have enough information to say with any certainty that there will be only certain aspects of VHL in a family, which is why we recommend screening for all.¹

People sometimes say "she can’t have VHL because she doesn’t resemble the side of the family where the gene is." But those other traits have nothing to do with the gene for VHL, so we can’t rely on those as a way of guessing who may or may not be affected.

If you’ve had one clear screening, we cannot say with any certainty that that will continue to be true. We have to continue screening regularly throughout a person’s lifetime.

Seeing a Genetics Professional

Some people think they don’t need to see a geneticist because they have already made their child-bearing decisions. Evaluating one’s reproductive risks is the most common reason, but there are also other areas where genetics professionals may assist you in understanding and coping with complicated medical and genetic information, far beyond reproductive risks.

A genetic counseling session is an interactive process that often happens over a number of sessions. In addition to in-person visits there are often followup letters and phone calls, gene testing, summaries, and explanations.

Many people who call the hotline say, why do I need a genetics professional? Can’t my ophthalmologist or neurosurgeon submit the test? But a specialist is usually focused on the issues in their sub-specialty. The genetics professional can take the broader view and tie all the pieces together, and explain why all these various organs may need to be evaluated, and help you understand much of this complex information. While the primary purpose is not to evaluate reproductive risks, that is certainly a topic that can be explored, including providing test information during a pregnancy or discussing other approaches to having children to determine whether their child will have VHL or not. Another very important aspect of genetic counseling is to help the family cope with having a chronic genetic condition, making sure that over the years answers are provided and the right specialists are involved in a person’s care. In many of the clinical care centers (CCCs), including the one here at the Mayo Clinic, it is the genetics department that coordinates care among the various specialists for people with VHL and other multi-system genetic conditions.

People who call the hotline want to know how to find a genetic counselor, how do I find someone. In the US and Canada the certification is provided through the American Board of Genetic counseling, and the geneticists are certified through the American Board of Medical Genetics. Genetic counseling is most often available in teaching hospitals, associated with the department of pediatrics or obstetrics. A list is maintained on the internet by the National Society of Genetic Counselors (http://www.nsgc.org/).

People often ask who is going to pay for genetic counseling. Some insurance policies do cover genetic counseling and even genetic testing, but we have to evaluate it policy by policy. You can read your own policy or call the insurance carrier to determine the answer to the question. In most other countries, payment is not an issue. We have heard at this meeting about the registries maintained in many other countries with more centralized health care systems — France, Poland, Japan — where the genetics professionals will assist you in determining who else in your family tree might be at risk.

Often the hotline is asked, what is the role of a genetic counselor in a CCC? The CCC’s are institutions across the world that have volunteered to provide comprehensive services for VHL onsite, including genetic services. The genetic counselor can also help with coordinating appointments, making your visit as streamlined as possible, coordinating genetic testing, counseling with the practical issues that come up, and the emotional issues -- the fears and anxieties in the family.

Screening

When we think about screening of organs, who should be screened? Everyone who is at risk for VHL should be screened, including brothers and sisters and children of a person with VHL, and others identified in the pedigree: parents, aunt, uncles, and cousins.

Who should have DNA testing? Anyone who wants to clarify their personal risks for VHL. Sometimes people would prefer to go forward with clinical screening every year and would rather not know for sure whether they have the gene or not. It’s something that should be carefully thought through in advance. No one should be forced to have the test "It’s an easy blood test, just go for it!" But there are emotional issues, and each person has to be ready to hear the results.

What if I start this process, and then I change my mind? Do I have to know my result? No, it is your right not to know as well. If the lab has completed the testing we can’t tell them to destroy the results — the results will exist, but you don’t have to accept the resuIt. It doesn’t have to be shared with you until you are ready to learn that information.

Some people want to know what’s the best approach to learning the result: letter, phone call, or meeting. Our preference is to arrange an in-person visit to discuss the test results, and the implications of that information for their children and other family members. People almost always have other questions. It is important to make sure that the information is well understood, and to keep that avenue of information open for future questions.

Testing Children

At what age is it right to test a minor for VHL mutations? I don’t think there is a single right answer for this. We need to begin screening at an early age. If it were me, I would want to know whether there is a mutation or not, so I know whether to do this screening or not. But in other families this may not be the right answer, so this has to be individualized.

Should I share the results of genetic testing with my child and at what age? Again I think this has to be individualized to the family and the child. Clearly by the age of junior high school the child is clearly going to know that there is VHL in the family, and there is no reason to hide this information from them. They need to be undergoing screening, so they are going to know that something is going on. The gene result will probably help to clarify things for them, as long as it is explained in an age-appropriate way, and again this is a place where the genetic counselor can help.

Am I being a responsible parent by delaying gene testing? It has got to be a family’s decision, but if genetic testing is delayed I hope the parents will follow through with the screening. That untested child has to be considered at risk, and we have to continue the screening.

Communications

People have asked how to prepare for genetic testing. It is important to work this through with a genetics professional, to think through the implications not only for yourself but for others in the family. Sometimes people have surprisingly strong emotional reactions to the result – surprising even to themselves. "I came into this visit thinking I knew what the answer was going to be, and you’ve told me the opposite, and it’s just blown me out of the water." Other people say, "Well, it’s what I thought I was going to hear, but it’s impacting me more than I had expected."

What responsibility do we have toward other family members if we do test positive for VHL? In the medical community there is a clearly recognized "duty to warn." If someone comes in for VHL evaluation and has never had genetic counseling and doesn’t realize that others in the family may also be at risk for VHL, the genetic counselor has a responsibility to explain that to the patient. I think the patient has that same kind of moral duty toward their family members, to provide them with information to obtain the best health care they can.

What responsibility do I have to notify my ex-spouse about testing for our children? Again it needs to be individualized for the particular family. I would hope that both parents are still involved in the raising of their children, and both need to know the medical situation of their children.

Can the results of DNA testing be kept out of my medical record? And if so, how? I can tell you our policy here at Mayo, which is that any gene test result used for medical purposes and shared with the patient and physicians, will go into the medical record. That information needs to be available to all the people providing care for that person. Some institutions have in the past kept that information out of the medical chart, in order to keep it from being available to the insurance company or employer. Could this now become a "pre-existing condition" and something that would not be covered under the insurance policy? We would each need to check the fine print in the insurance policy. But it is becoming increasingly difficult to withhold this information from the insurance carrier, and there are more and better legal protections against abuse. In the case of someone who does carry the mutation, this information should become justification for the relatively expensive screening that it takes to manage this person’s health. This also helps them to avoid costly screening if they do not carry the gene.

You will undoubtedly have more questions that are unique to your own situation. The most important thing is to keep open the channel of information between you and a genetics professional so that as questions arise you can get the answers that you and your family need.

1. In fact one of the families who attended the conference had always believed that they only got brain and spinal cord issues. For three generations, that was all they had experienced. But in the course of the meeting they realized that the mysterious symptoms their 17-year-old daughter was experiencing were probably a pheochromocytoma. Testing showed that this was the case, and surgeons removed a pheo the size of a lemon.  See their story.

As printed in the VHL Family Forum 8:4, December 2000.  For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.