HealthMap

Facioscapulohumeral Muscular Dystrophy (FSHD) Genetics

• Not a typical gene mutation: Unlike many other muscular dystrophies caused by a faulty protein-coding gene, FSHD is primarily caused by an epigenetic abnormality and a genetic deletion on chromosome 4q35.
• D4Z4 Repeat Contraction (FSHD1): About 95% of cases (FSHD1) result from the contraction of a series of repetitive DNA segments called D4Z4 repeats. Healthy individuals typically have 11 to 100+ repeats, whereas people with FSHD have only 1 to 10 repeats.
• The DUX4 Gene: This repeat contraction leads to abnormal hypomethylation (loss of DNA methylation), which inappropriately activates the DUX4 gene. Normally, this gene is turned off in adult muscle tissue. Its toxic expression in muscle cells triggers a cascade of cellular damage and apoptosis.
• Chromosomal Region 4qA vs. 4qB: The disease-causing D4Z4 contraction only leads to FSHD if it occurs on a specific chromosomal background (known as the 4qA allele), which contains a polyadenylation signal necessary for the DUX4 mRNA to stabilize and cause toxicity.
• FSHD2 (Digenic Form): About 5% of cases (FSHD2) do not involve a major D4Z4 repeat contraction, but are instead caused by mutations in the SMCHD1 gene (located on chromosome 18). This gene is responsible for maintaining DNA methylation. Mutations here also lead to the same DUX4 hypomethylation and activation.