How Do I Read My FSHD Genetic Test Results?

When you read your Facioscapulohumeral dystrophy (FSHD) genetic test report, it might look like a confusing mix of letters and numbers. In plain English, this test is looking for a specific genetic combination that accidentally “unlocks” a gene called DUX4. This gene is normally permanently turned off in adult muscles, but when it is turned on, it produces a protein that is toxic to muscle cells ^[1][2]. To determine if this gene is active, the test measures two main things: the size of the genetic “lock” keeping the gene shut (measured in D4Z4 repeats), and the presence of a genetic stabilizer called 4qA ^[3].

Reading the Report: Two Copies of Every Gene

Because you inherit one set of chromosomes from each parent, your report will show results for two copies of chromosome 4. You only need one copy with a shortened lock and a 4qA stabilizer to develop FSHD. In medical terms, this is called autosomal dominant inheritance. This means a typical FSHD result will show one normal allele (for example, 35 repeats with 4qB) and one affected allele (for example, 5 repeats with 4qA) ^[4].

Note: Your report may also list D4Z4 repeats for Chromosome 10. Do not panic if you see a “contraction” on Chromosome 10. These repeats do not have the ability to make the toxic DUX4 protein, so contractions here are harmless and do not cause FSHD ^[4].

The Genetic “Lock”: D4Z4 Repeats at 4q35

Your DNA contains repeating sequences of genetic code near the end of chromosome 4, specifically in an area called 4q35 ^[3]. These sequences are called D4Z4 repeats. Think of this section of DNA as a heavy door with a chain lock that keeps the toxic DUX4 gene safely closed off ^[3].

The test report will provide a number (often called “repeat units” or “RUs”) indicating how many D4Z4 links you have on each of your two copies:

• Usually Normal Range (More than 20 repeats): In people without FSHD, this chain is long enough to keep the door firmly shut and the DUX4 gene turned off ^[4][5].
• Abnormal Range (1 to 10 repeats): If the chain is shortened (called a contraction) to between 1 and 10 repeats, the lock is too small to work properly. This allows the door to swing open, causing the most common form of the condition, known as FSHD1 ^[5][4].
• Intermediate Zone (11 to 20 repeats): This number of repeats is generally considered normal, but in some individuals, it can lead to FSHD2 (explained below) ^[4].

A note on severity: Research shows there is a statistical trend where a very low number of repeats (such as 1 to 3) is associated with symptoms appearing earlier in life ^[6][7]. However, FSHD is highly variable even within the same family. Your repeat number does not perfectly predict your individual disease course or severity.

The Genetic “Stabilizer”: Why 4qA Matters

Having a shortened D4Z4 chain at 4q35 is only half of the equation. For the DUX4 gene to actually produce the toxic muscle protein, it needs a specific genetic “ending” attached to it, which acts as a stabilizer. This ending is known as the 4qA allele (or 4qA haplotype) ^[8][3].

• 4qA (Permissive): This version of the gene includes the stabilizing instructions. If you have the 4qA ending and a shortened D4Z4 chain, the toxic DUX4 protein can be produced and survive in the muscles, leading to FSHD ^[9][3].
• 4qB (Non-permissive): This is a different version of the ending. If a person has 4qB instead of 4qA, the DUX4 instructions quickly break down and are harmlessly cleared away by the body before any toxic protein is made. Even if someone has a shortened D4Z4 chain (1 to 10 repeats), they will generally not develop FSHD if they only have the 4qB ending ^[3].

What if my repeats are in the intermediate zone? (FSHD2)

If your report shows a D4Z4 repeat number of 11 to 20, but you still have FSHD symptoms and the 4qA ending, you may have FSHD2 ^[4].

In FSHD2, the D4Z4 chain is long enough, but the actual physical “key” that tightens the lock is broken. This is most often caused by a mutation in a different gene called SMCHD1 ^[10][11]. The SMCHD1 protein normally helps pack the DNA tightly to keep DUX4 hidden. When it is mutated, the DNA stays loose and relaxed, allowing the DUX4 gene to turn on despite the normal-length chain ^[10]. While the genetic cause is slightly different, the end result—muscle damage from the DUX4 protein—is the same in both FSHD1 and FSHD2 ^[12][13].

Putting Your Results Together

When reviewing your test results with your care team, look for these two crucial pieces of information on chromosome 4:

1. The number of D4Z4 repeats: Is one of the alleles between 1 and 10 (pointing to FSHD1)?
2. The 4q status for that allele: Does it say 4qA (which allows the condition to develop)?

Understanding these components can help you and your doctor better predict your care needs. Because genetics can be complicated, it is highly recommended to review these results with a certified genetic counselor, especially before discussing testing with family members.