What causes FSHD?
FSHD (Facioscapulohumeral Muscular Dystrophy) is a genetic condition that weakens muscles. There are two types:
- FSHD Type 1 (FSHD1) – The most common type, caused by missing genetic material on chromosome 4.
- FSHD Type 2 (FSHD2) – Caused by a change in the SMCHD1 gene on chromosome 18.
Both types lead to the activation of a gene called DUX4, which harms muscle cells. Both types of FSHD also have the same symptoms.
Does everyone with FSHD develop symptoms?
No. About 80% of people with the FSHD genotype will develop symptoms, while 20% who test positive are asymptomatic (do not have symptoms). Symptoms may appear later in life or be so mild they go unnoticed.
Is genetic testing needed to diagnose FSHD?
An experienced doctor can diagnose someone with FSHD through a physical exam with a high degree of accuracy, but a genetic test is needed to know for sure. Testing will also determine whether a person has Type 1 or Type 2. A genetic test is also required to take part in research studies and clinical trials, as well as to be prescribed any future treatments that target the genetic cause of FSHD.
Why do symptoms vary among family members?
Severity and onset depend on genetic and non-genetic factors. Researchers are still studying what influences progression.
What is the risk of inheriting FSHD?
- FSHD1: A child of an affected parent has a 50% chance of inheriting it.
- FSHD2: The risk depends on both parents’ genetics but is at least 25-50%.
Genetic counseling can provide a clearer picture based on family history.
Can FSHD skip a generation?
FSHD does not skip generations, but some individuals may never develop symptoms while their children do, making it seem like the condition skipped a generation.
Who should get genetic testing?
Testing may be helpful if you:
- Have FSHD symptoms and want to confirm the type.
- Have a family history of FSHD but no symptoms.
- Are planning to have children and want to understand the risk.
- Want to be eligible to participate in a clinical trial.
- Want to have access to future treatments.
A genetic counselor can help you decide if testing is right for you.
How can someone get a genetic test for FSHD?
A doctor, nurse practitioner, or genetic counselor must order a blood test. Testing is available at specialized labs like the University of Iowa Diagnostic Laboratory and Revvity Omics.
What if insurance won’t cover the test?
Your doctor or genetic counselor can help appeal a denial. You can use our letter template help with your appeal. If not covered, you may consider paying out-of-pocket. Some labs offer financial assistance programs.
Will genetic testing affect life or disability insurance?
Health insurance is protected under the Genetic Information Nondiscrimination Act (GINA), but life and disability insurance are not. Some people choose to get insurance before genetic testing. Individuals with FSHD have successfully appealed the denial of life insurance by arguing that FSHD does not shorten life expectancy significantly.
The Affordable Care Act and the Americans with Disabilities Act also provide protections for people affected by or at risk for genetic conditions. 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.
Can someone without a genetic test join a research study?
It depends on the study. Contact the study coordinator to ask if testing is required.
What if genetic tests for FSHD1 and FSHD2 are negative, but an individual has all the classic symptoms of FSHD?
- Ensure you had the most up-to-date tests for both types.
- Other muscle conditions may have similar symptoms. A neuromuscular specialist can recommend broader genetic testing.
- Research on FSHD genetics is ongoing, and new findings may emerge. Contact the FSHD Society if you would like to have your genetics analyzed by a research laboratory.
What are options to prevent passing FSHD to children?
- Preimplantation Genetic Testing (PGT): Tests embryos before pregnancy using in vitro fertilization (IVF). This method requires DNA from the affected parent and an affected grandparent, sibling or child.
- Prenatal Testing: Tests during pregnancy (CVS or amniocentesis) to check if the baby has FSHD.
- Donor Eggs/Sperm: Ensures the child does not inherit FSHD.
- Adoption or Surrogacy: Alternative ways to build a 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. Talk to a genetic counselor to learn more about all of these options, including the advantages, disadvantages, limitations, and risks so you can make the choice that’s right for you.
Why should someone see a genetic counselor?
Genetic counselors are healthcare professionals with specialized training in genetics and psychological counseling. A genetic counselor helps you:
- Understand FSHD and your test results.
- Learn about family risk.
- Make informed decisions about testing and family planning.
- Find coping strategies for living with FSHD.
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.
Where can I find a genetic counselor?
Ask your neuromuscular specialist or search www.findageneticcounselor.com. There are also “telehealth companies such as Genome Medical that employ licensed genetic counselors who provide consultations by phone or video.
Where can I get a genetic test?
Your doctor can order genetic testing through one of the services listed below. FSHD testing is more complicated than most, so we have provided contacts that can answer questions your doctor may have. These labs do not offer direct patient consultation.
For a complete list of genetic testing labs worldwide, visit:
North America
Bionano Laboratories (U.S.)
Website: bionanolaboratories.com
Revvity Omics (U.S.)
Website: https://www.revvity.com/category/clinical-genomic-services
Contact Form: https://www.revvity.com/contact-us
University of Iowa Diagnostic Laboratories (U.S.)
Client Services Phone: (866) 844-2522
Mary Sue Otis, UI Diagnostic Laboratories Manager.
Email: marysue-otis@uiowa.edu Phone: (319) 356-3339 Fax: (319) 384-7213.
Steven A. Moore, MD PhD, Professor of Pathology.
Email: steven-moore@uiowa.edu Phone: 319-335-8215.
Testing offered:
- Whole genome optical mapping test for FSHD1; FSHD2 SMCHD1 sequencing; methylation testing (for FSHD1 and FSHD2). Details and requisition forms available here: Detection of Abnormal Alleles with Interpretation (FSHD1 and FSHD2). Read the press release about Bionano’s Saphyr optical mapping technology used for this test.
- Prenatal diagnosis and 4qA/4qB allele testing. Prenatal specimens should be cultured to 100% confluency in 6 T-25 flasks and must not be frozen.
- Overseas clients can send specimens to UIDL via FedEx overnight using this International MD Requisition Form. The lab requires payment prior to testing. Credit cards accepted.
Praxis Genomics (U.S.)
- Optical Genome Mapping (OGM) can determine whether the patient has FSHD1 and whole genome sequencing using Illumina technology (ISR) can diagnose FSHD2. At Praxis Genomics, we offer testing for FSHD1 and FSHD2 individually, as well as in combination. View their test list.
Quest/Athena Diagnostics (U.S.)
Contact: Carol A. Hoffman, Ph.D., M.S., LCGC. Genetic counselor, genomic services.
Phone: +1.774-843-3135| fax +1.508.318.4068| carol.hoffman@athenadiagnostics.com
Testing offered: Currently not available. The company is validating optical whole genome mapping and plans to make FSHD testing available in the future.
Children’s Hospital of Eastern Ontario Molecular Genetics Diagnostic Laboratory (Canada)
Canada Director: Nancy Carson, PhD, FCCMG
Email: carson@cheo.on.ca Phone: (613) 737-7600, Ext. 3282 Fax: (613) 738-4822
Europe and UK
University of Leiden (The Netherlands)
CHU de Marseille – Hôpital de la Timone (France)
Molecular Genetics Laboratory (8ème étage)
Department of Medical Genetics
264 rue Saint-Pierre
13385 Marseille cedex 05
Contact : Dr. Rafaëlle Bernard-Rolain
Tel : +33 4 91 38 46 06
Email : rafaelle.bernard@ap-hm.fr
Website
Clinical Institute for Genomic Medicine, University Medical Center Ljubljana
UZ Leuven, Belgium
Geneve Hospital, Switzerland
Genetica, Switzerland
Southwest Genomic Laboratory Hub (UK)
Asia
Pangenia Genomics (website). (Hong Kong)
Read the blog post about this laboratory and Pangenia Center of Excellence for Rare Diseases (PanRARE).
Unit 1380, 13/F, KITEC, 1 Trademart Drive, Kowloon Bay, Hong Kong
Phone: (+852) 3989 6160 Fax: (+852) 2147 4138
Email: info@panrare.com
AMCARE Genomics Laboratory (China)
Unit 201, Block 4-C, Phase 2
International Biological Island
No. 9, Luoxuan 4th Road
Guangzhou, Guangdong 510300 China
Contact : Dr. Victor Wei Zhang
Tel : +86 020-34397241
Email : victor.w.zhang@amcarelab.com
Website: www.amcarelab.com
Koc University Hospital Genetic Diseases Evaluation Center, FSHD R&D Unit
We offer Bionano optical genome mapping (OGM) testing for FSHD1 and NGS testing for FSHD2. Please fill in the request form at https://www.kuh.ku.edu.tr/genetic and we will contact you for detailed information.
Koc University Hospital, Genetic Diseases Evaluation Center
Maltepe Mahallesi and Davutpaşa Caddesi
No: 4 Topkapı, 34010 Istanbul / Turkey
T:+90850 250 8 250, T:+90212 467 87 00
Contact e-mail: genetik@kuh.ku.edu.tr
Website: https://www.kuh.ku.edu.tr/our-centers/muscular-diseases
I had a test done but can’t find my report. What should I do?
If you have previously been tested by Athena/Quest or the University of Iowa, you should be able to contact the lab and ask for a copy to be sent. They will require a signed consent form so that they can release the test report to you.
Athena/Quest Diagnostics, call the Customer Service Department at 1-800-394-4493 Option 2.
University of Iowa, call Client Services at (866) 844-2522.
How is FSHD genetic testing done?
The individual being tested needs to provide a DNA sample, usually collected by a blood draw. DNA can also be obtained from skin, saliva (containing cells from the mouth), etc. But for genetic testing, a blood sample is standard.
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. This shortened, or “contracted”, chromosome must be combined with a “permissive” 4qA polyadenylation site in for the DUX4 gene to be expressed in a stable form. When this happens, it leads to damage and death of muscle cells.
For many years, the standard test for FSHD1 involved a technology called Southern blot, which involves taking a patient’s DNA, 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.
More recently, a technology called whole genome optical mapping has made it possible 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.
The genetic test report gives two numbers, for Allele 1 and Allele 2 (for the two copies each person has of chromosome 4). Depending on the type of testing method, you may receive a report providing the number of D4Z4 repeats, or with an estimated size of the D4Z4 region (measured in kilobases).
The genetic test for FSHD2 consists of sequencing a gene called SMCHD1 on chromosome 18 to detect all variants or mutants that have been could contribute to FSHD2. In addition, chromosome 4 is tested for the presence of the “permissive” 4qA allele.
This decision tree (above right) depicts how FSHD genetic testing is carried out. (Reference: Tawil, et al., Neurology 2015)
If you have tested negative for FSHD1
You should ask to be tested for FSHD2. The test is available through Revvity Omics and the University of Iowa. If you are negative for both FSHD1 and FSHD2, you may wish to be screened by Revvity Omics comprehensive neuromuscular disease panel or for other muscular disorders through Invitae’s comprehensive neuromuscular disorders panel.
About 2 percent of FSHD cases are of unknown genetic origin. If your tests rule out any known genetic muscle diseases, please contact us . We can connect you with researchers who are interested in collecting DNA samples from you to try to identify novel genes that cause FSHD and other muscle diseases.
Interpreting FSHD1 Southern blot test results
The Southern blot test was once the gold standard. People who were tested for FSHD before 2020 probably had this type of test.
The test report for FSHD1 provides a report of the estimated size (measured in kilobases) of the DNA fragment containing the D4Z4 repeat region. A report might look like this:
| Enzymes |
EcoRI |
EcoRI/Blnl |
| Allele 1 |
>40 kb |
>40 kb |
| Allele 2 |
18 kb |
15 kb |
To make sense of the test results: Both of the individual’s alleles (one from each chromosome 4) is being tested for FSHD. First, each DNA strand is cut with an enzyme called EcoRI and then further checked to see if it is an unusual arrangement of DNA with another enzyme called BlnI which further cuts the DNA .
The results show an unaffected chromosome 4 (Allele 1) and affected chromosome 4 (Allele 2). D4Z4 repeat numbers were calculated from EcoRI-fragment sizes by this formula:
(Fragment size minus 5) divided by 3.3 = the number of repeats
On Allele 1, the length of this segment is greater than 40 kilobases (kb) and, therefore, according to the formula above, the estimated number of repeats is 10.6 (because (40 – 5)/3.3., or 35/3.3, equals 10.6) and so it is in the not-FSHD range. Allele 2 is 4 repeats (because (18 – 5)/3.3, or 13/3.3, equals 4), which indicates FSHD.
Is there an association between the size of the deletion on chromosome 4 and the severity of FSHD in an individual?
There does appear to be a relationship between the size of the deletion and the severity and age of onset of FSHD. Large deletions (resulting in very small fragments) appear to be associated with earlier onset and more severe symptoms. Also, large deletions are more likely to be sporadic rather than inherited. Small deletions tend to be associated with later onset and milder symptoms. But research has also shown exceptions to this trend. What this implies is that there are additional factors, which may be genetic or environmental, that influence how severe an individual’s symptoms will be.
How accurate is DNA testing for FSHD?
About 98 percent of individuals with FSHD can be accurately diagnosed by the DNA test. Within some FSHD families, some individuals have a deletion but do not show obvious symptoms of FSHD. This situation is more likely to occur when the number of D4Z4 units is close to normal. Intriguingly, 1-2 percent of individuals in the general population without FSHD show the same deletion (loss of D4Z4 units) in the same region of chromosome 4. The significance of this finding, in an Italian population, is not yet understood.
I have symptoms of FSHD. How can I arrange for a DNA test to confirm FSHD?
You can ask your doctor to refer you to your local genetics clinic. There, a detailed family history will be taken. The geneticist will be able to identify those individuals in your family who could most benefit from DNA testing. The geneticist will also be able to arrange for the blood sampling and shipment of the blood to a testing center.
The DNA test results are reported to the referring physician (usually a geneticist). Since DNA test results can be difficult to interpret and understand, it is essential to have a skilled professional, such as a geneticist, explain the results of DNA testing.
What Is meant by sporadic or “de novo” FSHD and inherited FSHD?
Sporadic or “de novo” (meaning “new”) FSHD means a single individual in a family has FSHD, but no one else in the family has the condition. To prove a case is sporadic, both parents would need to be genetically confirmed to not have the D4Z4 deletion. Because individuals can have the D4Z4 deletion and not show symptoms, if both parents have not been tested, a seemingly sporadic case could in fact be inherited.
I have FSHD. What is the risk that I could have a child with FSHD?
Individuals with FSHD Type 1 have a 50 percent chance of passing FSHD to each child. With Type 2, two genes on separate chromosomes (SMCHD1 on chromosome 18 and the polyA haplotype on chromosome 4) must both be inherited to transmit FSHD, so the risk is smaller, 25-50 percent depending on the parents’ genetic makeup.
We have been told that our child has sporadic FSHD. Is there any risk FSHD could occur in our next child?
Up to 20 percent of apparently sporadic cases of FSHD arise due to mosaicism for the FSHD deletion in one parent. This means that one parent has a mixture of cells: some with the deletion and some without the deletion. If the deletion occurs in the egg or sperm cells of the parent, but other cells in the body do not have the deletion, a genetic test (e.g. from blood or skin) of the parent would show no FSHD, and yet the parent can pass FSHD on to multiple offspring. Therefore, there is a risk of having another child with FSHD, even if there is no detectable deletion in either parent.
Is there a prenatal test for FSHD?
Yes. Using the same technology as in the DNA test described above, prenatal testing is possible. Those who are interested in a prenatal test for FSHD should consult their physician and the genetic testing laboratories.
In prenatal diagnosis, fetal cells are obtained primarily by one of two procedures. The earliest procedure is called chorionic villus sampling (CVS). This procedure is performed at about the tenth to twelfth week of pregnancy. The alternative procedure is called amniocentesis. This procedure is performed at about the fifteenth to sixteenth week of pregnancy. Individuals at risk of having a child with FSHD should see a geneticist for counseling as early as possible in the pregnancy or even before becoming pregnant, since it is necessary for their DNA to be tested in order to obtain accurate results. Prenatal diagnosis must be arranged many weeks in advance, through a genetics clinic. Prenatal tests have risks associated with them, and therefore it is important to obtain genetic counseling and consider all the information about prenatal testing carefully before deciding to proceed. In general, molecular diagnostic laboratories make a special effort to process prenatal DNA samples as rapidly as possible.
Is pre-implantation genetic diagnosis (PGD) available for FSHD?
Yes. This is a procedure in which in vitro fertilization is used to produce multiple embryos in a test tube. At the eight-cell stage, a single cell is removed and tested. Only embryos that test negative for FSHD are implanted. An important aspect to know about PGD is that because only one strand of DNA is available for testing, the number of D4Z4 units cannot be directly determined. Instead, DNA from the affected parent and another affected relative is analyzed for “markers” located close to the D4Z4 region. The embryonic DNA is then analyzed for the presence of those markers. Because parts of chromosomes can get rearranged, sometimes the marker and the D4Z4 region are not inherited together, so this method is not 100 percent accurate. Therefore, if parents opt for PGD, a prenatal test is usually recommended as a follow-up to be sure the deletion was not passed on.
