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Genetics of Hemochromatosis

How to Climb your Medical Family Tree
How many times have you wondered who your ancestors were? What were they like? What did they look like? How did they live? How was their health? How did they die? It’s really not that difficult to discover who your ancestors were and what some of their health issues were if you know where to look. Here are some suggestions to get you started:

1.) Find the oldest relatives you have and interview them. Ask them for a medical family history. Ask them what conditions affected family members, and what the causes of death were for these family members. You will be surprised what you may find out.

2.) Collect death certificates for deceased family members. This may seem morbid, but it is an excellent source of information about your family members and their cause of death. The older the death certificate is, the more vague the reason for death may be. There may be words used to describe an illness that is no longer in current medical use. For instance, my grandfather Thomas, who was a medical doctor, died of “Brights Disease”. This is a term which is no longer used today, however, it means a form of kidney disease. I learned this from his death certificate. Other terms such as “Senility” might be used as a “cause of death”. That might have been an earlier term for “Alzheimer’s Disease” or simply a term used because the person was very elderly and really didn’t have any known medical problems. Some death certificates which are quite old will state that the cause of death was, “old age”. Obviously, these are not detailed medical accounts, however, many do list medical symptoms and causes which could be very helpful to you today and in considering your medical future.

3.) Contact some hereditary societies such as the Daughters of the American Revolution (DAR) www.dar.org or the Sons of the American Revolution (SAR) www.sar.org which help people trace their ancestors back to the American Revolution. There are many such organizations. The DAR and SAR have excellent resources for tracing your family history. You can purchase “pedigree forms” to build your family tree and obtain excellent genealogical (study of your family tree) kits which instruct you how to trace your family.

4.) Talk to family members and get the names, dates of birth, marriage and death for as many family members as possible. This will give you a sound foundation upon which to gather medical information.

5.) After obtaining basic data on family members, find out what medical problems family members have had. Notate similarities in various family members.

6.) Visit www.ancestry.com and www.ngsgenealogy.org/index.htm for an overview of genealogy.

Tracing your medical history
Now that you have gather basic information and written it on a pedigree form (or made up a chart for that purpose), you can start tracing your medical history. There are many sources to obtain a genetic chart which will show you how to notate males and females, those living and deceased and adults and children. This is how genetic counselors create personalized “charts” for their patients, outlining their potential risks for any given disease, based often on the health of other family members and/or actual genetic testing results.

You don’t have to make up a fancy medical chart though, to discover your medical history and plot your medical future in many ways. Start with yourself, and work your way back up your family tree. For instance, write your name down at the top of a page of paper or at the top of the page on your computer. List your medical conditions and symptoms. Moving down the page to the next line, list your parents, the father first, then the mother on the next line. List their medical problems and continue in this manner as far back as you can go.

If you wish, you can include siblings (brothers and sisters) of yours and of each parent on your way back in time. Move on to your grandparents, and great grandparents. It will become a fascinating hobby to collect this information and may, along the way, end up saving your life and the lives of others in your family.

Tracing your medical history using genetics
We are now moving into an era of genetic testing. Once reserved for rare diseases and only offered at select clinics and teaching universities, genetic testing has become more and more mainstream in recent years. Genetic testing is still in its infancy, yet it has come a long way in the last five years. The Human Genome Project has been completed and the public is becoming more aware of genetics and genetic testing thanks to the media coverage this topic has generated.

Genetic testing, however, in the past, has often revealed serious and deadly diseases, diseases for which, at this time in medical history, there is no treatment or cure. Because of this fact, many people have not wanted to “know” their genetic status for these diseases, and rightfully so. However, there is a positive side of genetic testing which is emerging. Such an example is screening genetically for hereditary hemochromatosis, also known as HFE-associated hereditary hemochromatosis or genetic iron overload. In 1996, the gene mutation, known as HFE, was discovered and a commercial test developed for it. This test, in my opinion, is one of the most exciting medical breakthroughs to come along in a long time. Unfortunately, most people and their doctors are unaware that this testing is so readily available and so reasonably priced.

To trace your family tree using genetic testing for hemochromatosis is simple and can become a “family project” that will bring families together in a very special way. Because hemochromatosis is treatable and preventable, many of the issues surrounding other genetic diseases do not apply to hemochromatosis and families affected by it.

The American Hemochromatosis Society recommends genetic screening for every man, woman, and child in the United States. By identifying even one person in a family who has the gene mutation for hemochromatosis (cys282 or his63 gene mutations), you can begin a screening process of the entire family and identify family members who are at genetic risk long before they ever become symptomatic.

There is a simple DNA genetic test kit which can be used for adults or children. It is painless and the results are ready in 24 hours from the time of the receipt of the sample. The sample is gathered by simply rubbing the inside of your cheek with a mascara type wand and takes only a few minutes to complete. Even the cost is reasonable compared with the cost of other genetic tests (the hemochromatosis test kit is $125 vs. the colon cancer test kit which is thousands of dollars).

Will genetic testing be covered by insurance? That depends on your insurance company so you will need to discuss that with them. However, if you are willing and able to pay out of pocket, the hemochromatosis test kit is available directly to the health consumer from the lab to the patient. No doctor’s order is needed and a copy of the report is send directly to you the patient.

Now, how do you interpret the results and how do they apply to your family tree? You start with yourself (or the diagnosed person in your family) and genetically test them. Write down their results on your pedigree so that you will have a good overview of the entire family. This could be done with other types of genetic tests as well.

There are some basic concepts about genetic testing for hemochromatosis. I will describe them in very simple terms for easier understanding. Naturally, anyone wishing a more complex, scientific explanation can explore MEDLINE or other resources for detailed molecular discussions of this same topic. Most people want a basic idea of what the results mean. I have developed the following information over the past seven years that I have been discussing genetic test results with patients and have found that they usually understand it very well.

The basics of genetic testing for hemochromatosis
Hereditary hemochromatosis (HH) is the build up of toxic amounts of iron in vital body organs. Hereditary hemochromatosis is also known as HFE-associated hereditary hemochromatosis, also known as genetic iron overload or iron storage disease.

There are two major mutations which cause excess iron to be stored in vital body organs. The gene mutation is called “HFE” thus the term HFE-associated hereditary hemochromatosis. These two gene mutations are called:

cys282 also known as C282 gene mutation. People often call this gene mutation “cys” (pronounced “siss”) for short. Example: “I carry the cys282 gene mutation” or “Do you have the cys mutation?”

his63 also known as H63 gene mutation. People often call this gene mutation “his” (pronounced “hiss”) for short. Example: “His mother has a double his” or “His doctor tested him for the cys and his gene mutations”.

There are some other gene mutations for hemochromatosis which have been recently discovered and may be involved in the uptake of iron in the gut which is then stored in the liver, pancreas, heart, joints, and brain. However, for the purpose of this lesson, we will focus only on the two major gene mutations which are usually used in genetic tests commercially at this time. (Note: Some labs call the cys mutation the “major mutation” and the his mutation the “minor mutation”. We feel that both mutations contribute to iron storage. Therefore, they are both “major mutations” in our book.

What combinations of gene mutations can you have for hemochromatosis?

You can have the genetic test and your results can come back as follows:

Negative. You do not have either the cys or his gene mutation.

Positive for one gene mutation which is known as a “heterozygote” or “het” for short. Example: “He must be a heterozygote because he has one cys mutation”.

Positive for two gene mutations which is known as a “homozygote”. Example: “She is a homozygote for the his mutation”.

You can have two cys282 gene mutations (usually considered the highest risk for loading and storing iron at some point in your life) or two his63 gene mutations. Both of these configurations of results are associated with iron loading and storage.

You can have one cys282 and one his63 gene mutation at the same time. This is known as a “compound heterozygote” or “compound het” for short. Example: “Her daughter is a compound het”.

You can load and store excess iron even if you have one mutation (het status), but usually not as much as if you were homozygous status (double gene mutation).

How do you get these gene mutations? You inherit them from your parents. If you have one gene mutation, you have inherited it from either your mother or your father. There is no way to know which one without testing your parents.

If you have two gene mutations (making you a homozygote or a compound heterozygote), you have inherited one mutation from your mother and one from your father. You cannot inherit two gene mutations from one parent. If you have two gene mutations, you have inherited one from each parent.

If you have two gene mutations, you must pass one of them to all of your children, no matter how many children you have. Nature dictates this rule. Why? Because when you have two gene mutations, nature dictates that you must pass one, no more, no less, gene mutation to all of your offspring, no matter what gender they are.

If you have one gene mutation, then nature says that you may, or may not, pass that gene mutation to your children. It is a spin of the roulette wheel; you have no way of knowing if you will pass that gene mutation or not when you just have one and you have no control whatsoever over that passing of the gene to your offspring.

If you and your spouse are genetically tested, and both are negative, then all of your children will be negative. This is known without testing your children.

If you are a homozygote (double gene mutation) and your spouse is negative, then all of your children with that spouse will be heterozygotes (single gene mutation). This is known without testing the children.

If you are a homozygote (double gene mutation) and your spouse is a heterozygote (single gene mutation), then the children will need to be tested to know their status, because even though we know that the homozygote has passed one mutation to all children, we do not know if the heterozygote has passed the one gene mutation to the children. Therefore, the children have to be at least all heterozygotes, but if any of the children have also inherited a single gene mutation from the other parent, then that child(ren) would be a homozygote also. A heterozygote has a 50% chance of passing a gene mutation to the children, however, statistics are just that--statistics. I highly recommend that families test their children when the parents have this genetic makeup.

If you are a heterozygote and your spouse is a heterozygote, then your children must be tested to know their status. Possible outcomes of test results for the children could range from negative to homozygote or any combination thereof, including all negative, or all homozygote, or some negative, some heterozygote, and some homozygote. Only genetic testing could tell for sure.

If you are a homozygote and your spouse is also a homozygote, then you do not need to test your children, for all of them will also be homozygotes, having inherited one mutation from each parent giving them the double gene mutation status known as homozygote.

Males and females inherit these mutations at the same rate. These gene mutations do not “skip generations”.

Many people want to know their risk for iron overload if they have the gene mutations. The answer is that there are many factors involved in having iron overload when you have the gene mutations, some things prevent iron overload that you do in your life, and other things encourage it. The best thing you can do is acquaint yourself with those things which increase or decrease your chances of loading excess iron in your body. It is possible that you could have the gene mutations and not get iron overload, and it is also possible to have iron overload and not have the two major mutations for hemochromatosis. Researchers believe that there are other gene mutations which are probably involved in iron overload/hemochromatosis which have yet to be discovered.

It is for these reasons, that the American Hemochromatosis Society not only recommend screening everyone genetically for hemochromatosis, but also testing their iron storage status annually using transferrin saturation percentage (TS) and serum ferritin.

If a patient has a positive result for the genetic testing (single or double gene mutation status) and elevated iron studies (a TS greater than 40% and/or a ferritin greater than 150ng/ml), then hereditary hemochromatosis should be seriously considered and further evaluation taken by the physician and the patient.

This information is a very simplistic representation of genetic testing and how to interpret the results. It is not intended to be academic in any sense, but rather a quick and easy way to understand your genetic test results.

I’ve got my genetic test results, now what to do next?
Now that you have your genetic test results, you can combine that information with your TS and ferritin test results.

If your TS/ferritin tests are abnormal, further evaluation should take place. If your genetic test is positive in any way (single or double gene mutation), but your TS/ferritin tests are normal, you can start monitoring yourself at least annually to make sure that the iron levels are not rising to an abnormal level. You can also take preventive steps to avoid iron storage in your future and to nip it in the bud should it occur.

Armed with your genetic test results and annual TS/ferritin screening, you should never, ever have to be ill or die from hemochromatosis. And, that is indeed good news.

Anyone wishing to discuss their test results with me is welcome to contact me by email at: mail@americanhs.org or call me directly at: 407-829-4488. Have your genetic test results in front of you so that we can discuss the exact results. You should also have your TS/ferritin results at diagnosis and your most recent screening as well. You should discuss your test results with your doctor or genetic counselor if you have any questions as well.

Climbing your family tree is fun and easy. Turning that family tree into a medical family tree can not only be fun, but life-saving, not only for you, but for generations to come.

Sandra Thomas, President, American Hemochromatosis Society