FSHD Type 1 Testing (D4Z4 repeat size)

• Molecular confirmation of a clinical diagnosis of FSHD
• Clinical suspicion of FSHD and previous neuromuscular panel did not yield a diagnosis

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by muscle weakness and wasting. This condition gets its name from the muscles that are affected most often: those of the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). The signs and symptoms of FSHD usually appear in adolescence. However, the onset and severity of the condition vary widely. Milder cases may not become noticeable until later in life, whereas rare severe cases become apparent in infancy or early childhood. Weakness involving the facial muscles or shoulders is usually the first symptom of this condition. Facial muscle weakness often makes it difficult to drink from a straw, whistle, or turn up the corners of the mouth when smiling. Weakness in muscles around the eyes can prevent the eyes from closing fully while a person is asleep, which can lead to dry eyes and other eye problems. For unclear reasons, weakness may be more severe on one side of the face than the other. Weak shoulder muscles tend to make the shoulder blades protrude from the back, a common sign known as scapular winging. Weakness in the shoulders and upper arms muscles can make it challenging to raise the arms over the head or throw a ball. The muscle weakness associated with FSHD worsens slowly over decades and may spread to other body parts. Weakness in muscles of the lower legs can lead to a condition called foot drop, which affects walking and increases the risk of falls. Muscular weakness in the hips and pelvis can make climbing stairs or walking long distances difficult. Additionally, affected individuals may have an exaggerated lower back curvature (lordosis) due to weak abdominal muscles. About 20 percent of affected individuals eventually require the use of a wheelchair. Additional signs and symptoms of FSHD include mild high-tone hearing loss and retinal abnormalities. These signs are often not noticeable and may only be discovered during medical testing. FSHD rarely affects the heart or respiratory muscle. Researchers have described two types of FSHD: type 1 (FSHD1) and type 2 (FSHD2). Both types have the same signs and symptoms and are only distinguished by their genetic cause.

The Bionano EnFocus FSHD Analysis is performed based on whole-genome optical mapping data collected on the Bionano Genomics Saphyr Genome Imaging Instrument. Based on specific labeling and mapping of ultra-high molecular weight DNA in nanochannel arrays, optical mapping enables high-resolution analysis of the D4Z4 repeat array. Molecules aligning to regions of interest in chr4 and chr10 are extracted and assembled. The resulting consensus maps are used for the Bionano EnFocus FSHD Analysis. The repeat arrays are sized, and the permissive and non-permissive alleles (4qA and 4qB) are assigned. This method cannot detect single-nucleotide variants that do not impact sequence motif sites and may miss small variants with potential functional impacts.