Julie Cohen, ScM, genetic counselor in the Center for Genetic Muscle Disorders at the Kennedy Krieger Institute in Baltimore, Maryland, answers some commonly asked questions.
Q. What is the genetic cause of FSHD?
Let me begin by saying that the genetics of FSHD is quite complex! There are two types of FSHD, called Type 1 and Type 2. The two types are distinguished based on their underlying genetic cause. The symptoms are the same in both types.
FSHD Type 1 (FSHD1) is by far the most common, accounting for about 95 percent of people with FSHD. FSHD1 is caused by a deletion of genetic material on chromosome 4. More specifically, the deletion affects a region called the D4Z4 region that is located near the end of the long arm of chromosome 4 called 4q35. Individuals with FSHD1 have the deletion plus a genetic marker called the “4qA haplotype.”
FSHD Type 2 is caused by a change in a gene called SMCHD1 that is located on chromosome 18. Individuals with FSHD2 have an SMCHD1 gene change plus the 4qA haplotype.
Both types of FSHD result in expression of a gene called DUX4 that is normally supposed to be turned off. It is thought that expression of DUX4 is harmful to muscle cells. There is still a great deal of research going on to better understand the genetic causes of FSHD and the role of DUX4.
Q. Does everyone with the FSHD “mutation” develop symptoms?
No, not everyone with an FSHD-associated genetic change (FSHD genotype) will show symptoms of FSHD. Based on current knowledge, it is estimated that about 80 percent of individuals with the FSHD genotype will show symptoms, whereas 20 percent will be asymptomatic. We don’t know why some people show symptoms and others do not. There likely are other genetic and nongenetic factors playing a role. Importantly, if you have the FSHD genotype but are asymptomatic, you can still pass it on to a child who may show symptoms. Also, keep in mind that some people may have very subtle signs of FSHD that can only be noticed by a doctor, or their symptoms may not become apparent until later in life.
Q. Is a genetic test needed to diagnose FSHD?
Yes, genetic testing is needed to definitely diagnosis FSHD and determine whether it is Type 1 or Type 2. Once one person in a family has had genetic testing to confirm the FSHD diagnosis, other affected family members may be diagnosed based on clinical findings without genetic testing. Relatives who have subtle findings or unclear symptoms may need genetic testing to confirm or rule out an FSHD diagnosis.
Q. Why are some family members more severely affected than others?
Severity of symptoms and age of onset are influenced by various genetic and nongenetic factors, including the D4Z4 deletion size, methylation of the D4Z4 region, and SMCHD1 mutations. These and other as-yet-unknown factors are active areas of research in FSHD. At this time, it is not possible to make predictions about severity, progression or age of onset for an individual based on their genetic test result.
Q. If someone without symptoms has a close family member with FSHD, what is their risk of also having FSHD?
FSHD1 is inherited in an autosomal dominant pattern, which means that children of an individual with FSHD1 have a 50 percent chance that they inherited the FSHD1 genotype. Parents of an individual with FSHD1 may have the deletion, or the deletion may have occurred new (de novo) in the affected individual. The risk to siblings of an individual with FSHD1 depends on whether the deletion was inherited from a parent (in which case the risk is 50 percent that the sibling has the FSHD1 genotype) or de novo (in which case there still is a risk to the sibling, due to the possibility of germline mosaicism, meaning that the deletion could be present only in a parent’s egg or sperm cells). Because people can have the FSHD genotype but not manifest symptoms, the only sure way of knowing one’s risk is by genetic testing. I always recommend that first-degree relatives of an individual with FSHD consider genetic testing if they want to know their risk.
The inheritance pattern of FSHD2 is not as straightforward, because it requires inheriting two different genetic changes (the SMCHD1 variant on chromosome 18 and the 4qA haplotype on chromosome 4), which are independent of one another. For a child of an individual with FSHD2, the risk of having an FSHD2 genotype also depends on the genotype of the other, unaffected parent. The risk for the child is at minimum 25 percent, but could be 50 percent depending on the genotypes of the parents.
As you can see, this is all quite complicated! A genetic counselor familiar with FSHD can give you more precise risk information based on your family’s unique situation.
Q. Can FSHD “skip” a generation?
FSHD can appear to skip generations because some people with the FSHD genotype do not show symptoms. However, the genetic change does not skip generations. Also, it should be noted that the deletion size does not change when passed from generation to generation.
Q. Who should consider genetic testing for FSHD?
There are several scenarios in which I would recommend genetic testing for FSHD. Of course, the decision to undergo genetic testing is a personal one.
- If you have a clinical diagnosis of FSHD and are the only person in your family who has been diagnosed, or if you have a clinical diagnosis of FSHD and a family history of the disease, but none of your affected family members have had genetic testing to determine if it is Type 1 or Type 2. In these situations, genetic testing would be needed to confirm the FSHD diagnosis and establish if it is Type 1 or 2.
- If you have a family history of confirmed FSHD Type 1 or 2, but there is uncertainty in your diagnosis: for example, if you have some symptoms but your doctor isn’t sure whether they are related to FSHD.
- If you have a close family member with confirmed FSHD Type 1 or 2 and you would like to know your risk, even if you do not have any symptoms.
- If you have a clinical diagnosis of FSHD, and a family history of confirmed FSHD Type 1 or 2, and are interested in using prenatal testing or in vitro fertilization with preimplantation genetic diagnosis to have children.
Q. If someone has a genetic test showing they have FSHD, who else in the family should consider getting tested?
Close relatives (parents, siblings, children) of an individual with confirmed FSHD should consider genetic testing. I strongly recommend that anyone considering genetic testing should speak with a genetic counselor first to learn about the benefits, limitations, and risks of finding out their status. Genetic testing in asymptomatic children is generally not recommended; rather, it is usually best to wait until the child is older and can participate in decision-making about undergoing the genetic test for FSHD.
Q. How does an individual get a genetic test for FSHD?
Genetic testing for FSHD is done on a blood sample and usually must be ordered by a doctor or nurse practitioner. In some US states, genetic counselors can order genetic testing. Currently, there is only one laboratory in the United States that offers comprehensive genetic testing for both types of FSHD: the University of Iowa Diagnostic Laboratory. You should see a neuromuscular specialist and/or genetic counselor experienced in FSHD. They will be able to coordinate your testing, including working with your insurance company, and organizing sample collection and shipment to the genetic testing laboratory.
Q. If a health insurance company refuses to cover a patient’s genetic test cost on the grounds that it would not affect medical care, how should the patient respond?
Your genetic counselor or neuromuscular specialist should help advocate for you to your health insurance company. There are many ways in which establishing a definite genetic diagnosis of FSHD would impact medical care. For example, individuals with FSHD need to be screened for retinal problems and hearing loss so that these problems can be detected and treated early. It should also be noted that establishing a diagnosis of FSHD can avoid unnecessary treatments or procedures, such as cardiac screening (since FSHD does not cause heart problems, whereas other types of muscular dystrophy do affect the heart). Genetic testing is also necessary for accurate counseling about recurrence risk and to utilize reproductive options (see below), as well as to identify other at-risk relatives.
Q. Someone who has a family risk of FSHD but has no symptoms currently might have difficulty getting insurance coverage for the test. What can they do?
Again, I really recommend that you work with a genetic counselor or neuromuscular specialist who is willing to go to bat for you with your health insurance company. If your insurance won’t cover the test, you could consider paying out of pocket.
Q. Some people are afraid to get a genetic test because it might make getting life insurance or long-term disability insurance difficult or impossible to obtain. What are their options?
The Genetic Information Nondiscrimination Act (GINA) offers a number of protections against discrimination in health insurance and employment, but GINA does not address other types of insurance such as life, disability, or long-term care. The Affordable Care Act and the Americans with Disabilities Act also provide protections for people affected by or at risk for genetic conditions. In addition, some states have laws that prohibit genetic discrimination for these other types of insurance. More information about genetic discrimination and related laws can be found here.
If you get insurance before having genetic testing, the results can’t affect your coverage. For this reason, many people decide to get their insurance coverage first. If you have already had genetic testing, that doesn’t mean you won’t be able to get any insurance. Some insurance companies may not ask about genetic testing or require review of medical records during the application and underwriting process. I recommend researching different insurance companies and options.
Q. If a patient hasn’t had a genetic test, can they still volunteer for a research study or clinical trial?
If there is a particular study or trial that you are interested in, contact the coordinator to find out if genetic testing is a requirement.
Q. Some individuals have all the classic symptoms of FSHD but test negative for FSHD1 and FSHD2. What options do they have to try to get a genetic diagnosis?
First, make sure that you had comprehensive testing for both types of FSHD. Testing for FSHD2 has only been available for the past few years, so individuals who were tested prior to then may not have actually been tested for FSHD2.
If comprehensive testing for FSHD1 and FSHD2 has been completed with negative/normal results, it may be appropriate for you to have genetic testing for other forms of muscular dystrophy (MD), some of which have features that may overlap with FSHD. Seek out an evaluation with a neuromuscular doctor who specializes in genetic muscle disorders. They may recommend additional genetic testing with a multi-gene panel (which includes a large number of genes associated with different types of MD), or perhaps exome sequencing (a broad genetic test that looks at the important parts of nearly all ~20,000 genes).
Q. For individuals who are concerned about passing FSHD on to children, what are the options?
Individuals who want to have children but wish to prevent passing on FSHD have several options.
- A popular option is preimplantation genetic testing (PGT). This is genetic testing of embryos created by in vitro fertilization (IVF). Cells from the embryos are tested to determine which ones have the FSHD genotype and which do not. Only embryos predicted to be unaffected with FSHD would be transferred to the woman’s womb to begin the pregnancy. There is a small chance of error with PGT, so prenatal testing is often also recommended to confirm the result (see below). At this time, PGT for FSHD1 is usually only possible for individuals who have inherited the deletion from a parent, or for people who already have had a child. If you are interested in using PGT, you should consult with a genetic counselor to find out if PGT is an option for you and learn more details about what the process involves. IVF and PGT are very expensive, but your health insurance company may cover some or all of the cost.
- Another reproductive option is prenatal testing. This is genetic testing done during a pregnancy to determine if the fetus (unborn baby) has FSHD. If the testing shows that the fetus has FSHD, the couple could choose to terminate the pregnancy. There are two procedures for prenatal testing: chorionic villus sampling (CVS) and amniocentesis. CVS is performed at the end of the first trimester of pregnancy (11-13 weeks’ gestation). The doctor uses a catheter through the woman’s cervix, or a needle through her abdomen, to obtain a small sample of tissue from part of the placenta. Amniocentesis is performed in the second trimester of pregnancy (16-20 weeks’ gestation). The doctor uses a needle inserted through the woman’s abdomen to obtain a small amount of amniotic fluid. Genetic testing is performed on the CVS sample or the amniotic fluid. Prenatal testing is highly accurate, but the procedures are associated with a small risk of miscarriage (fewer than one in 200, or 0.5 percent).
- Some people with FSHD decide to use donor eggs or donor sperm to conceive their children, thus ensuring that their offspring would be unaffected since the donor does not have FSHD. The downside to this option is that the children would not be genetically related to both parents. Donated eggs can be used for IVF. Donated sperm can be used for IVF or artificial insemination.
- Adoption is another option that some people choose to create their family.
Women with FSHD must be aware that pregnancy can cause increased muscle weakness, which usually does not go back to baseline. For this reason, some women choose to use a gestational carrier (surrogate). In this option, an embryo or embryos created by IVF (either using the woman’s own eggs or donor eggs) are transferred to the womb of another woman who carries the pregnancy to term. Women with FSHD should speak to their neuromuscular specialist prior to becoming pregnant.
Individuals and couples consider many different factors when deciding how to build their family. Remember that there is no “correct” option that is right for everyone. Talk to a genetic counselor to learn more about all of these options, including the advantages, disadvantages, limitations, and risks.
Q. Why should an individual consult a genetic counselor?
Well, I think everybody should see a genetic counselor, but I am biased! Genetic counselors are healthcare professionals with specialized training in genetics and psychological counseling. One misconception is that genetic counseling is only for people making decisions about having children and using reproductive testing options. In fact, people in all different situations and points in their lifespan may benefit from genetic counseling. For example, a genetic counselor can help you:
- understand the genetic cause of FSHD and your specific test results;
- learn the chances for your children or other family members to have FSHD;
- figure out how to talk to your children or relatives about their risk for FSHD;
- decide whether or not to have genetic testing, and what the results might mean for you;
- make family planning and reproductive testing decisions; and
- discover coping strategies for living with FSHD.
Q. How can I or my relatives find a genetic counselor?
Your neuromuscular specialist may be able to recommend a genetic counselor at their hospital or nearby. Otherwise, you can find a genetic counselor by searching on the website of the National Society of Genetic Counselors at www.findageneticcounselor.com. There are also “tele-genetics” companies that employ licensed genetic counselors who provide consultations by phone or video.