Your doctor can order a genetic test for FSHD. Before seeking a test, consult a genetic counselor to make sure you fully understand the process and have considered how you and your family will respond to the information revealed by the test results.
- To understand some of the issues that may come up, read our article FAQs about genetic testing for FSHD, by genetic counselor and FSHD expert Julie Cohen, MSc.
Commercial genetic tests are available for FSHD Type 1 and Type 2. If you already have a family member who has been tested, find out what type of FSHD they had (get a copy of their report if possible), as you will only need to be tested for that type. If you don’t have a family member who has been diagnosed, you will usually be tested for Type 1 first because around 95 percent of cases are Type 1. If you test negative for Type 1, you may inquire about obtaining a test for FSHD Type 2 or for a broader panel of neuromuscular conditions.
- To understand the types of FSHD genetic testing that are available, and the difference between research and clinical testing, read Genetic testing for FSHD-A new frontier.
Insurance companies may refuse to cover genetic testing in family members who may be asymptomatic but at risk of having, and passing along, the FSHD gene. If that happens, use this letter template to file an appeal:
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.
- Southern blot testing is available at the University of Iowa and Quest Diagnostics.
- Whole genome optical mapping is now available from Perkin Elmer.
For a complete list of genetic testing labs worldwide, visit:
- Online International Directory of Genetic Testing Laboratories – search for FSHD and click on the “Test” tab.
- NCBI Genetic Testing Registry – Click on “Test” link
Perkin Elmer Genomics
Website: perkinelmergenomics.com
Phone: 866-354-2910
Email: Genomics@perkinelmer.com
Testing offered:
- FSHD1 by whole genome optical mapping
- FSHD2 by full sequencing and deletion/duplication analysis of the SMCHD1 gene utilizing next-generation sequencing.
- FSHD Type 1 and Type 2 panel
- Comprehensive neuromuscular panel (including FSHD2 but NOT FSHD1)
- Comprehensive neuromuscular panel including FSHD1 testing
University of Iowa Diagnostic Laboratories
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:
- FSHD1 4q35 deletion detection by PFGE and Southern blot analysis & 4qA/4qB allele determination; FSHD2 SMCHD1 sequencing; methylation testing (for FSHD1 and FSHD2). Details and requisition forms available here: Detection of Abnormal Alleles with Interpretation (FSHD1 and FSHD2).
- 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 clientscan send specimens to UIDL via FedEx overnight using this International MD Requisition Form. The lab requires payment prior to testing. Credit cards accepted.
Quest/Athena Diagnostics
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:
Children’s Hospital of Eastern Ontario Molecular Genetics Diagnostic Laboratory
Canada Director: Nancy Carson, PhD, FCCMG
Email: carson@cheo.on.ca Phone: (613) 737-7600, Ext. 3282 Fax: (613) 738-4822
University of Leiden, the Netherlands
- Testing for FSHD1 and FSHD2 can be ordered through Leiden University in the Netherlands. It takes about eight weeks for results to be reported. Download the University of Leiden genetic test request form (pdf).
Current Procedural Terminology (CPT) is a medical code set that is used to report medical, surgical, and diagnostic procedures and services to entities such as physicians and health insurance companies. When filing a claim of genetic testing, you may be asked to provide this code. In addition, the testing company or insurer may ask for the ICD-10 code for FSHD. It is G71.02.
Testing company | Test type | CPT Code |
PerkinElmer Genomics D8000 | FSHD Type 1 Testing (D4Z4 repeat size) | 81404x1 |
PerkinElmer Genomics D8001 | FSHD Types 1 and 2 Panel | 81404x1, 81479x1 |
PerkinElmer Genomics D8002 | Complete Neuromuscular Disease Panel with FSHD Type 1 Testing | 81407x1, 81408x1,81161x1, 81405x1, 81406x1, 81404x2 |
Quest/Athena 17029 | FSHD1 Southern Blot Test | 81404 |
University of Iowa ZB5J4 | FSHD1 Southern Blot Test | 81404 |
University of Iowa ZB5J4 | FSHD2 sequencing of SMCHD1 & D4Z4 methylation assay | 81479 |
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)
You should ask to be tested for FSHD2. The test is available through PerkinElmer Genomics and the University of Iowa. If you are negative for both FSHD1 and FSHD2, you may wish to be screened by Perkin Elmer’s comprehensive neuromuscular disease panel or for limb-girdle muscular dystrophies through Invitae’s limb-girdle genetic testing program.
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.
The Southern blot test 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/BlnI |
| Allele 1 | >40 kb | >40 kb |
| Allele 2 | 18 kb | 15 kb |
To make sense of the test results: Each one of the inquirer’s chromosome 4’s is being tested for FSHD. First they are cut with an enzyme called EcoRI and then further checked to see if it is an unusual arrangement of DNA with another enzyme which further cuts the DNA called BlnI.
The results show the inquirer’s unaffected chromosome 4 (Allele 1) and affected chromosome 4 (Allele 2). D4Z4 repeat numbers were calculated from EcoRI-fragment sizes by this formula:
The number of repeats = (fragment size minus 5) divided by 3.3.
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 greater than 10.6 (because (40 – 5)/3.3., or 45/3.3, 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.
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.
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 deletion is small (i.e. the number of D4Z4 units is closer 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.
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.
Sporadic 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.
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 in order to transmit FSHD, so the risk is smaller, 25-50 percent depending on the parents’ genetic makeup.
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.
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.
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 other affected relatives 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.
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.