Genetic testing for FSHD—a new frontier

Several genetic diagnostics labs now offer a test called whole-genome optical mapping for FSHD Type 1. Some also offer a neuromuscular panel that includes FSHD Type 2. These are major advances in FSHD molecular diagnostic testing that are now available for your doctor to order.

A genetic test for FSHD is now being offered by Revvity Omics, a global company known for scientific and medical testing services (FSHD Type 1 Test) (FSHD Type 2 Test). Other companies and groups are likely to follow suit. This is the first major innovation in FSHD genetic testing in nearly three decades to “reach the clinic”—available for your doctor to order.

For patients and families, this development has a number of advantages:

• This new test for FSHD Type 1 is expected to be 2-3 times less expensive than current alternatives;
• The company offers a comprehensive test for 132 other neuromuscular conditions including FSHD Type 2 in addition to the FSHD Type 1 assay;
• The test includes genomics support to your physician to explain what the test means for you and your family.

This article explains why this is such an important advancement in FSHD testing, and also puts into the context of the bigger picture of how innovations in genetic testing can affect research and clinical trials.

Why seek a genetic test?

Usually, a doctor will diagnose facioscapulohumeral muscular dystrophy (FSHD) based on taking a family history and examining the patient for symptoms. For many doctors, the prevailing mindset has been that “there’s no treatment or cure,” so the added expense of having the diagnosis confirmed by a genetic test is not warranted.

Today, a doctor’s diagnosis is still perfectly valid, but there are some compelling reasons to also have a genetic test. Among them:

1. The genetic test is definitive, especially if you have unusual symptoms that may cast some doubt on your diagnosis;
2. You can avoid expensive and painful procedures (such as muscle biopsy and electromyography), as these are useful only for ruling out other conditions and do not confirm whether you have FSHD;
3. Knowing your diagnosis for certain may help you plan for the future;
4. You and your family can make informed decisions about who else in the family should get tested, how the diagnosis affects family-planning, and so forth;
5. Some clinical studies or trials require that volunteers have their FSHD diagnosis confirmed by a genetic test;
6. The FDA could require that some future treatments be allowed only for patients who have had a genetic test.

For a more in-depth understanding of whether you may wish to seek genetic testing for you and/or your family, please read our FAQs about genetic testing for FSHD by genetic counselor Julie Cohen, MSc. She has counseled hundreds of families at the Kennedy Krieger Institute, one of the world’s leading research centers for genetic muscle diseases.

How is the new test different?

The cause of FSHD lies in our genome, the DNA molecules that are bundled up into 23 chromosomes residing in the nucleus of the cells in our bodies. Our genomes contain the “genetic code”—the molecular compendium of instructions that make us human and unique.

FSHD Type 1 results from the shortening (“contraction”) of a stretch of DNA near the tip of chromosome 4. The “FSHD region” on chromosome 4 consists of many units called D4Z4, which are repeated like beads on a string. Having more than 10 beads is protective, but if an individual has fewer than 10, and he/she is at risk for FSHD. The reduced number of D4Z4 units results in an increased chance for the expression of a gene called DUX4, which is normally locked up and silent in adult cells. When DUX4 gets expressed, it leads to damage and death of muscle cells.

For many years, the test for FSHD1 involved a technology called Southern blot (named after its inventor, the English biologist Edwin Southern). This technology involved taking a patient’s DNA (typically extracted from blood cells), chopping the long DNA strands into smaller pieces and separating the pieces by their size. The DNA pieces would then be transferred to a membrane and probed to roughly estimate the number of D4Z4 repeats.

Southern blots take a lot of labor and time and, at best, provide an estimate of the number of repeats. With the revolution in DNA sequencing technology, the cost of reading the sequence of the 3 billion “letters” in the human genome has plummeted to under $1,000. FSHD testing, however, did not benefit from these advances because of the nature of FSHD genetics. While typical genetic conditions are caused by “typos” (or mutations) in the DNA and can be found quickly with a “spell checker,” the D4Z4 contraction is more like missing repetitive paragraphs. You can’t find it using a spell checker.

Now all this is changing with the new test. Using a technology called whole genome optical mapping, developed by Bionano Genomics, scientists are able to examine very long strands of DNA which are stretched out like pieces of thread in a super-thin tube and probed with a fluorescent tag to directly count the number of D4Z4 units under a microscope. Whereas the Southern blot method is time-consuming and can only estimate the number of D4Z4 units, whole genome optical mapping is faster and more exact.

Research versus clinical tests

A question that comes up often in our community is what to do if a person cannot get a genetic test through their doctor? There are a variety of reasons why this situation could arise, including:

• The doctor won’t order the test;
• Insurance won’t cover the cost;
• The individual doesn’t want the genetic test result in their medical record.

If, based on symptoms or family history, a person qualifies to join an FSHD research study or clinical trial, they may have an opportunity to have a genetic test done at no cost. Each research study has its own goals and protocols, so it’s important to understand what kind of testing is being offered and how that information can or cannot be used.

Volunteers participating in the National Registry for FSHD at the University of Rochester, for example, can have their DNA tested in the Netherlands. (The FSHD Society and Friends of FSH Research have funded this program.) A positive test helps genetically confirm your doctor’s clinical diagnosis. However, since it was not done in a certified commercial lab in the United States, it is not considered as an official genetic confirmation. Nevertheless, someone with a positive test is more likely to be considered for a research study or trial where a certified genetic confirmation will be obtained for confirmation once they are in the study.

Another opportunity for patients and families to have genetic testing as part of a research study is through the laboratory of Peter and Takako Jones, at the University of Nevada Reno. Their test is based on the “methylation” of the D4Z4 region. “Methylation” is a molecular tag on the DNA that normally keeps genes from being expressed.  In unaffected people, the D4Z4 regions are “hypermethylated” or heavily tagged, but in FSHD1 or FSHD2, there are fewer tags (“hypomethylation”) which leads to an increased risk of DUX4 becoming expressed and causing disease. This test can be done using saliva samples that are collected in a special tube and simply mailed back to the Jones lab.  People don’t have to get their blood drawn. The test is still experimental, and the Jones lab is in the process of collecting samples from 1,000 volunteers, including individuals with FSHD, their healthy family members, and people with other neuromuscular conditions.

“We cannot promise you will benefit from being in this study,” notes the study’s informed consent form. “However, if you choose to have the research results returned to you, you may learn if you have the genetics and/or epigenetics consistent with a neuromuscular disease and the identity of that disease. This would allow you to seek appropriate clinical expertise and support.” The methylation test is viewed as highly promising by scientists, but there is not a broad consensus yet that it can serve as an FSHD diagnostic test on its own.

Genetic testing has been an area of great concern for the FSHD Society as patients and families have not been served well by the high cost of the Southern Blot Test. And this poses a serious problem for research. Just a few years ago, nearly half of the individuals in the national registry had not had a genetic test. Without genetic proof, the rest of their data is of limited value. The large percentage of patients who have not had genetic testing also slows down recruitment for clinical trials. As such, it is a high priority to develop a genetic testing system that is affordable and accessible to patients and families while capturing data that researchers need in order to better understand FSHD and develop treatments.

One possible scenario is for a fast, inexpensive test to screen individuals for hypomethylation of the D4Z4 region. Those that have low methylation consistent with FSHD would be referred for more comprehensive testing for the number of D4Z4 repeats and the presence of other mutations or genetic modifiers. Patients could agree in advance to allow their genetic and clinical data to be studied for research. The data from such a system would yield invaluable insights for new treatments and future clinical trials. Our goal is to bring together the scientists, companies, patient advocates, and other stakeholders to make this vision a reality.

Getting tested

As noted above, if you choose to get tested as part of a research study, the test findings cannot be included in your medical record. If you at some point need your genetic diagnosis in your medical record, you would need to be re-tested using a clinical test. Rabi Tawil, MD, director of the Fields Center for FSHD Research at the University of Rochester, explained some reasons to have a clinical test, including:

• Being able to enroll in a clinical trial;
• If someone shows no signs of FSHD but has an affected parent or sibling and they are still at risk of having FSHD. Having a positive or negative test may help guide their family planning;
• In the future, being able to receive medications that block DUX4, which might be approved only for patients with genetically confirmed FSHD.

Both the Southern blot and whole genome optical mapping tests are currently available to patients. Some of the diagnostic labs that currently offer Southern blot are also developing tests based on whole genome optical mapping, so stay tuned for updates.

• Southern blot testing is available at the University of Iowa and Quest Diagnostics.
• Whole genome optical mapping is now available from Revvity Omics, the University of Iowa, and Bionano Genomics.

If you are able to travel to be seen at an FSHD Clinical Trial Research Network (CTRN) clinic, we encourage it. They will have the expertise to do a proper clinical diagnosis, order appropriate genetic testing, and tell you about the latest studies and clinical trials.

If you aren’t able to be seen at a CTRN, contact your local FSHD Society chapter or headquarters to find out if there are knowledgeable doctors in your area.

If your health insurance balks at covering the genetic test, use our letter template to help you appeal your case.

DISCLAIMER: Information provided by the FSHD Society does not imply an endorsement of any of the drugs, procedures, treatments, or products discussed. Please consult your own healthcare provider about any medical interventions.